Pyrazinone derivatives

ABSTRACT

The present invention relates to pyrazinone derivatives of formula (I): 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are as herein defined; processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

The present invention relates to pyrazinone derivatives, processes fortheir preparation, pharmaceutical compositions containing them and theiruse in therapy.

The essential function of the lungs requires a fragile structure withenormous exposure to the environment, including pollutants, microbes,allergens, and carcinogens. Host factors, resulting from interactions oflifestyle choices and genetic composition, influence the response tothis exposure. Damage or infection to the lungs can give rise to a widerange of diseases of the respiratory system (or respiratory diseases). Anumber of these diseases are of great public health importance.Respiratory diseases include Acute Lung Injury, Acute RespiratoryDistress Syndrome (ARDS), occupational lung disease, lung cancer,tuberculosis, fibrosis, pneumoconiosis, pneumonia, emphysema, ChronicObstructive Pulmonary Disease (COPD) and asthma.

Among the most common of the respiratory diseases is asthma. Asthma isgenerally defined as an inflammatory disorder of the airways withclinical symptoms arising from intermittent airflow obstruction. It ischaracterised clinically by paroxysms of wheezing, dyspnea and cough. Itis a chronic disabling disorder that appears to be increasing inprevalence and severity. It is estimated that 15% of children and 5% ofadults in the population of developed countries suffer from asthma.Therapy should therefore be aimed at controlling symptoms so that normallife is possible and at the same time provide basis for treating theunderlying inflammation.

COPD is a term which refers to a large group of lung diseases which caninterfere with normal breathing. Current clinical guidelines define COPDas a disease state characterized by airflow limitation that is not fullyreversible. The airflow limitation is usually both progressive andassociated with an abnormal inflammatory response of the lungs tonoxious particles and gases. The most important contributory source ofsuch particles and gases, at least in the western world, is tobaccosmoke. COPD patients have a variety of symptoms, including cough,shortness of breath, and excessive production of sputum; such symptomsarise from dysfunction of a number of cellular compartments, includingneutrophils, macrophages, and epithelial cells. The two most importantconditions covered by COPD are chronic bronchitis and emphysema.

Chronic bronchitis is a long-standing inflammation of the bronchi whichcauses increased production of mucous and other changes. The patients'symptoms are cough and expectoration of sputum. Chronic bronchitis canlead to more frequent and severe respiratory infections, narrowing andplugging of the bronchi, difficult breathing and disability.

Emphysema is a chronic lung disease which affects the alveoli and/or theends of the smallest bronchi. The lung loses its elasticity andtherefore these areas of the lungs become enlarged. These enlarged areastrap stale air and do not effectively exchange it with fresh air. Thisresults in difficult breathing and may result in insufficient oxygenbeing delivered to the blood. The predominant symptom in patients withemphysema is shortness of breath.

Therapeutic agents used in the treatment of respiratory diseases includecorticosteroids. Corticosteroids (also known as glucocorticosteroids orglucocorticoids) are potent anti-inflammatory agents. Whilst their exactmechanism of action is not clear, the end result of corticosteroidtreatment is a decrease in the number, activity and movement ofinflammatory cells into the bronchial submucosa, leading to decreasedairway responsiveness. Corticosteroids may also cause reduced sheddingof bronchial epithelial lining, vascular permeability, and mucussecretion. Whilst corticosteroid treatment can yield important benefits,the efficacy of these agents is often far from satisfactory,particularly in COPD. Moreover, whilst the use of steroids may lead totherapeutic effects, it is desirable to be able to use steroids in lowdoses to minimise the occurrence and severity of undesirable sideeffects that may be associated with regular administration. Recentstudies have also highlighted the problem of the acquisition of steroidresistance amongst patients suffering from respiratory diseases. Forexample, cigarette smokers with asthma have been found to be insensitiveto short term inhaled corticosteroid therapy, but the disparity of theresponse between smokers and non-smokers appears to be reduced with highdose inhaled corticosteroid (Tomlinson et al., Thorax 2005; 60:282-287).

A further class of therapeutic agent used in the treatment ofrespiratory diseases are bronchodilators. Bronchodilators may be used toalleviate symptoms of respiratory diseases by relaxing the bronchialsmooth muscles, reducing airway obstruction, reducing lunghyperinflation and decreasing shortness of breath. Types ofbronchodilators in clinical use include β₂ adrenoceptor agonists,muscarinic receptor antagonists and methylxanthines. Bronchodilators areprescribed mainly for symptomatic relief and they are not considered toalter the natural history of respiratory diseases.

The serine/threonine kinase, p38, is a member of the stress and mitogenactivated protein kinase family (SAPK/MAPK) and participates inintracellular signalling cascades involved in a number of responsesassociated with inflammatory processes. Four isoforms of p38 kinase areknown to exist, identified as p38α, p38β, p38γ and p38δ.

The p38 pathway is activated by stress (including tobacco smoke,infections or oxidative products) and pro-inflammatory cytokines (e.g.IL-1 or TNF-α) and is involved in induction of cytokines such as TNF-α,IL-1, IL-6 and matrix metalloprotease by bacterial lipopolysaccharide(LPS). Activation of p38 by dual phosphorylation of thr¹⁸⁰ and tyr¹⁸²located in the activation loop is achieved by two dual specificityupstream MAP kinase kinases (MKK); MKK3 and MKK6. In turn p38phosphorylates numerous targets including other kinases andtranscription factors. In addition to effects on transcription, p38 isinvolved in the control of mRNA stability of several cytokines includingTNF-α, IL-3, IL-6 and IL-8. Thus through this cascade, p38 kinase isthought to play a significant role in the control of transcription andtranslation responsible for the induction of pro-inflammatory genes andthe subsequent release of pro-inflammatory cytokines such as TNF-α fromcells. This mechanism has been validated by investigation of the effectsof inhibiting the p38 kinase enzyme on chronic inflammation andarthritis (Kumar et al, Nature Reviews Drug Discovery (2003) 2:717-725). In particular, p38 kinase inhibitors have been described aspotential agents for treating rheumatoid arthritis.

In addition to the links between p38 activation and chronic inflammationand arthritis, there is also data implicating a role for p38 in thepathogenesis of airway diseases in particular COPD and asthma. Stressstimuli (including tobacco smoke, infections or oxidative products) cancause inflammation within the lung environment. Inhibitors of p38 havebeen shown to inhibit LPS and ovalbumin induced airway TNF-α, IL-1-β,IL-6, IL-4, IL-5 and IL-13 (Haddad et al Br J Pharmacol, 2001, 132 (8),1715; Underwood et al., Am J Physiol Lung cell Mol 200, 279, L895; Duanet al., 2005 Am J Respir Crit Care Med, 171, 571; Escott et al Br JPharmacol., 2000, 131, 173; Underwood et al., J Pharmacol Exp Ther. 293,281). Furthermore, they significantly inhibit neutrophilia and therelease of MMP-9 in LPS, ozone or cigarette smoke models. There is alsoa significant body of preclinical data highlighting the potentialbenefits of inhibition of the p38 kinase that could be relevant in thelung (Lee et al. Immunopharmacology, 2000, 47, 185-200). Thus,therapeutic inhibition of p38 activation may be important in theregulation of airway inflammation. Efficacy is anticipated when p38kinase inhibitors are administered either locally to the lung (forexample by inhalation and intranasal delivery) or via systemic routes(for example, oral, intravenous and subcuteanous delivery).

A particular aspect of the present invention relates to pharmaceuticalcompositions that are formulated to allow the compounds described hereinto be administered locally to the lung. Advantages associated with suchinhaled drug delivery include large lung surface area for doseabsorption; rapid drug absorption, rapid onset of action; avoidance ofthe gastrointestinal tract and first-pass metabolism, lower dose andreduced side effects.

Known inhibitors of p38 kinase have been reviewed by G. J. Hanson inExpert Opinions on Therapeutic Patents, 1997, 7, 729-733, J Hynes et alCurrent Topics in Medicinal chemistry 2005, 5, 967-985, C Dominguez etal in Expert Opinions on Therapeutic Patents, 2005, 15, 801-816.

The present invention provides a compound of formula (I):

wherein:R¹, R^(1a) and R² are independently selected from H, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo, CF₃, and CN;R³ and R⁴ are independently selected from H, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo, OH, NR⁸R⁹, CF₃, CN, aryl, heteroaryl and CONR¹⁰R¹¹,wherein said (C₁-C₆)alkyl and said (C₁-C₆)alkoxy are, independently,optionally substituted with 1, 2 or 3 groups independently selected fromOH, (C₁-C₃)alkoxy, NR¹²R¹³, S(O)_(p)R⁵⁵ and halo;R⁵ is selected from H, aryl, heteroaryl, heterocycloalkyl,(C₃-C₇)cycloalkyl, (CR¹⁴R¹⁵)_(m)NR¹⁶R¹⁷, S(O)_(p)R¹⁶, SO₂NR¹⁶R¹⁷, CH₂R¹⁶and OR¹⁶;R⁶ is selected from H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₇)cycloalkyl,—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl, heteroaryl and aryl; wherein said(C₁-C₆)alkyl may be optionally substituted by halo or OH;R⁷ is selected from H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₇)cycloalkyland aryl;or R⁶ and R⁷ together with the nitrogen atom to which they are attachedform a 4 to 7 membered ring, optionally containing a further heteroatomselected from NR¹⁸, S and O;

R⁸ and R⁹ are independently selected from H, (C₁-C₆)alkyl, (C₁-C₆)alkoxyand (C₃-C₆)cycloalkyl; or R⁸ and R⁹ together with the nitrogen atom towhich they are attached form a 4 to 7 membered ring, optionallycontaining a further heteroatom selected from NR¹⁹, S and O;

R¹⁴ and R¹⁵ are selected from H and (C₁-C₆)alkyl; or R¹⁴ and R¹⁵together with the carbon to which they are attached form a carbonyl(C═O) group;R¹⁶ is selected from H, aryl, (C₃-C₇)cycloalkyl and

wherein said (C₃-C₇)cycloalkyl may be optionally substituted with anaryl group;R¹⁷ is selected from H, (C₁-C₆)alkyl, aryl, heteroaryl, heterocycloalkyland (C₃-C₇)cycloalkyl, wherein said (C₁-C₆)alkyl may be optionallysubstituted with 1, 2 or 3 groups independently selected from(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, heteroaryl andNR²⁰R²¹;R²² is selected from H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, OH, NR²⁹R³⁰,heterocycloalkyl and aryl, wherein said (C₁-C₆)alkyl may be optionallysubstituted with 1, 2 or 3 R²⁸ groups; and wherein said aryl may beoptionally substituted with 1, 2 or 3 groups independently selected from(C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo, CF₃ and OH;R²³ is selected from H and (C₁-C₆)alkyl;or R²² and R²³ together with the carbon atom to which they are attachedform a (C₃-C₇)cycloalkyl or heterocycloalkyl ring;X is a bond or a (CR²⁴R²⁵)_(n) group;

R²⁴ and R²⁵ are independently selected from H, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, OH, heterocycloalkyl and NR³⁹R⁴⁰; or R²⁴ and R²⁵ togetherwith the carbon atom to which they are attached may form aheterocycloalkyl ring;

Z is an aryl or heteroaryl ring, wherein said aryl or heteroaryl ring issubstituted with R²⁶ and R²⁷;R²⁶ is selected from H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, OH, aryl, O-aryl,halo, heterocycloalkyl, O-heterocycloalkyl, heteroaryl, O-heteroaryl,cycloalkyl, O-cycloalkyl, S(O)_(p)R³⁴, NR³⁴R³⁵ and CONR³⁴R³⁵, whereinsaid (C₁-C₆)alkyl or said (C₁-C₆)alkoxy may be optionally substitutedwith 1, 2 or 3 groups independently selected from halo, OH,heterocycloalkyl or NR³⁴R³⁵;R²⁷ is selected from H, halo and (C₁-C₆)alkyl, wherein said (C₁-C₆)alkylmay be optionally substituted with 1, 2 or 3 halo groups;or R²⁶ and R²⁷ together may form a methylenedioxy group, when attachedto adjacent carbon atoms of the aryl or heteroaryl ring;each occurrence of R²⁸ is independently selected from NR²⁹R³⁰, halo,CH₂CF₃, CF₃, heterocycloalkyl, (C₁-C₆)alkoxy, OR³⁶, COOR⁴², CONR³¹R³²and SO₂NR³⁷R³⁸;R²⁹ and R³⁰ are independently selected from H, (C₁-C₆)alkyl,(C₃-C₇)cycloalkyl, SO₂R⁴¹ and C(O)R⁴¹, wherein said (C₁-C₆)alkyl may beoptionally substituted with, OH, NR⁵⁶R⁵⁷ or heterocycloalkyl;R³¹ and R³² are independently selected from H, (C₁-C₆)alkyl and(C₃-C₇)cycloalkyl; or R³¹ and R³² together with the nitrogen atom towhich they are attached form a 4 to 7 membered ring, optionallycontaining a further heteroatom selected from NR³³, S and O;R³⁴ and R³⁵ are independently selected from H, (C₁-C₆)alkyl,(C₃-C₇)cycloalkyl, C-linked heterocycloalkyl and C(O)O(C₁-C₆)alkyl,wherein said (C₁-C₆)alkyl may be optionally substituted by OH, halo,(C₁-C₆)alkoxy, NR⁵⁸R⁵⁹, C(O)OH and heterocycloalkyl; or R³⁴ and R³⁵together with the nitrogen to which they are attached form a 4 to 7membered ring;R³⁶ is selected from H, (C₁-C₆)alkyl and heterocycloalkyl, wherein said(C₁-C₆)alkyl may be optionally substituted with heterocycloalkyl;R¹⁰, R¹¹, R¹², R¹³, R¹⁸, R¹⁹, R²⁰, R²¹, R³³, R³⁷, R³⁸, R³⁹, R⁴⁰, R⁴¹ andR⁴² are independently selected from H and (C₁-C₆)alkyl;

-   -   m is 0 or 1;    -   n is 1 or 2;        each occurrence of p is independently selected from 0, 1 or 2;        cycloalkyl is a non-aromatic carbocyclic ring, optionally fused        to an aryl group, wherein said cycloalkyl ring optionally        contains, where possible, up to 2 double bonds; and wherein,        unless otherwise stated, said cycloalkyl may be optionally        substituted with 1 or 2 substituents independently selected from        (C₁-C₆)alkyl, (C₁-C₆)alkoxy, OH, CN, CF₃, halo and NR⁴³R⁴⁴;        heterocycloalkyl is a C-linked or N-linked 3 to 9 membered        non-aromatic, mono- or bi-cyclic ring, optionally fused to an        aryl or heteroaryl group group, wherein said heterocycloalkyl        ring contains:        1 or 2 NR⁴⁵ atoms, or        one N− atom, or        one N− atom and one NR⁴⁵, or        one N− atom, one NR⁴⁵ and an S(O)_(p) or an O atom, or        one N− atom and an S(O)_(p) or an O atom, or        one S atom, or        one O atom;        optionally containing, where possible, 1 or 2 double bonds; and        optionally substituted on carbon with 1 or 2 substituents        independently selected from (C₁-C₆)alkyl, (C₁-C₆)alkoxy, OH, CN,        CF₃, halo, ═O, NR⁴⁶R⁴⁷, —C(O)NR⁴⁶R⁴⁷, bivalent substituent        —OCH₂CH₂O— (wherein the terminal oxygen atoms are attached to        the same ring carbon atom), bivalent substituent —CH₂NHCH₂—        (wherein the terminal carbon atoms are attached to the same ring        carbon atom), a tetrahydro-1,1-dioxido-3-thienyl group, and        aryl, wherein said (C₁-C₆)alkyl may be optionally substituted by        aryl, (C₁-C₆)alkoxy or OH; and wherein each aryl group may be        optionally substituted with (C₁-C₆)alkoxy (which in turn may be        optionally substituted by NR³⁴R³⁵), (C₁-C₆)alkyl, OH, CF₃ and        halo;        aryl is an aromatic ring containing 6 or 10 carbon atoms;        wherein, unless otherwise stated, said aryl may be optionally        substituted with 1, 2 or 3 substituents independently selected        from (C₁-C₆)alkyl, (C₁-C₆)alkoxy, OH, halo, CN, CF₃ and NR⁴⁸R⁴⁹;        heteroaryl is a 5, 6, 9 or 10 membered aromatic ring, containing        from 1 or 2 N atoms and, optionally, an NR⁵⁰ atom, or one NR⁵⁰        atom and an S or an O atom, or one S atom, or one O atom;        wherein, unless otherwise stated, said heteroaryl may be        optionally substituted with 1, 2 or 3 substituents independently        selected from (C₁-C₆)alkyl, (C₁-C₆)alkoxy, OH, halo, CN, CF₃ and        NR⁵¹R⁵²;        R⁴⁵ is selected from H, (C₁-C₆)alkyl, C(O)(C₁-C₆)alkyl,        C(O)O(C₁-C₆)alkyl and aryl, wherein said (C₁-C₆)alkyl is        optionally substituted with a group selected from (C₁-C₃)alkoxy,        OH, halo, heterocycloalkyl and NR²⁹R³⁰; and wherein said        C(O)O(C₁-C₆)alkyl is optionally substituted with an aryl group;        R⁵⁰ is selected from H, (C₁-C₆)alkyl and C(O)O(C₁-C₆)alkyl,        wherein said (C₁-C₆)alkyl may be optionally substituted with a        group selected from (C₁-C₃)alkoxy, OH, halo, (C₃-C₆)cycloalkyl        and NR⁵³R⁵⁴;        R⁴³, R⁴⁴, R⁴⁶, R⁴⁷, R⁴⁸, R⁴⁹, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷        and R⁵⁹ are each independently selected from H and (C₁-C₆)alkyl;        R⁵⁸ is selected from H and (C₁-C₆)alkyl wherein said        (C₁-C₆)alkyl may be optionally substituted with a group selected        from (C₁-C₃)alkoxy and OH;        or a pharmaceutically acceptable salt thereof.

In another aspect the present invention provides a prodrug of a compoundof formula (I) as herein defined, or a pharmaceutically acceptable saltthereof.

In yet another aspect the present invention provides an N-oxide of acompound of formula (I) as herein defined, or a prodrug orpharmaceutically acceptable salt thereof.

It will be understood that certain compounds of the present inventionmay exist in solvated, for example hydrated, as well as unsolvatedforms. It is to be understood that the present invention encompasses allsuch solvated forms.

The present invention also comprises the following embodiments andcombinations thereof:

In one embodiment, the present invention provides a compound of formula(I) wherein R¹, R^(1a) and R² are independently selected from H,(C₁-C₄)alkyl, halo and CF₃.

In another embodiment, the present invention provides a compound offormula (I) wherein R¹, R^(1a) and R² are independently selected from H,(C₁-C₄)alkyl, F and Cl.

In yet another embodiment, the present invention provides a compound offormula (I) wherein R¹ and R^(1a) are independently selected from H, Fand CI and R² is selected from (C₁-C₄)alkyl, F and CI

In yet another embodiment, the present invention provides a compound offormula (I) wherein R¹ and R^(1a) are H and R² is selected from(C₁-C₄)alkyl, F and Cl.

In yet another embodiment, the present invention provides a compound offormula (I) wherein R¹ and R^(1a) are H and R² is methyl.

In another embodiment, the present invention provides a compound offormula (I) wherein R¹, R^(1a) and R² are independently selected from H,(C₁-C₄)alkyl and F.

In yet another embodiment, the present invention provides a compound offormula (I) wherein R¹ and R^(1a) are independently selected from H andF and R² is selected from (C₁-C₄)alkyl and F.

In yet another embodiment, the present invention provides a compound offormula (I) wherein R¹ and R^(1a) are H and R² is selected from(C₁-C₄)alkyl and F.

In yet another embodiment, the present invention provides a compound offormula (I) wherein R^(1a) is H, R¹ is F and R² is (C₁-C₄)alkyl.

In yet another embodiment, the present invention provides a compound offormula (I) wherein R^(1a) is H, R¹ is F and R² is methyl.

In one embodiment, the present invention provides a compound of formula(I) wherein R^(1a) is H.

In one embodiment, the present invention provides a compound of formula(I) wherein R^(1a) is H and R¹ and R² are independently selected from H,(C₁-C₄)alkyl, halo and CF₃.

In another embodiment, the present invention provides a compound offormula (I) wherein R^(1a) is H and R¹ and R² are independently selectedfrom H, (C₁-C₄)alkyl and F.

In yet another embodiment, the present invention provides a compound offormula (I) wherein R^(1a) is H, R¹ is selected from H and F and R² isselected from (C₁-C₄)alkyl and F.

In yet another embodiment, the present invention provides a compound offormula (I) wherein R^(1a) is H, R¹ is H and R² is selected from(C₁-C₄)alkyl and F.

In a yet further embodiment, the present invention provides a compoundof formula (I) wherein R^(1a) is H, R¹ is H and R² is methyl.

In one embodiment, the present invention provides a compound of formula(I) wherein R³ and R⁴ are independently selected from H, (C₁-C₄)alkyl,(C₁-C₄)alkoxy, Br, CI, F, CN, aryl and CONR¹⁰R¹¹, wherein said(C₁-C₄)alkyl and said (C₁-C₄)alkoxy are, independently, optionallysubstituted with 1, 2, or 3 groups independently selected from NR¹²R¹³and halo.

In another embodiment, the present invention provides a compound offormula (I) wherein R³ is H and R⁴ is selected from H, methyl, ethyl,methoxy, ethoxy, CI, Br, CN, phenyl and CONH₂, wherein methyl isoptionally substituted with a NR¹²R¹³ group. In yet another embodiment,the present invention provides a compound of formula (I) wherein R³ andR⁴ are H.

In one embodiment, the present invention provides a compound of formula(I) wherein R⁵ is selected from H, aryl, heteroaryl, NR¹⁶R¹⁷ andheterocycloalkyl.

In another embodiment, the present invention provides a compound offormula (I) wherein R⁵ is selected from heteroaryl, NR¹⁶R¹⁷ andheterocycloalkyl.

In yet another embodiment, the present invention provides a compound offormula (I) wherein R⁵ is selected from NR¹⁶R¹⁷ and heterocycloalkyl.

In a yet further embodiment, the present invention provides a compoundof formula (I) wherein R⁵ is NR¹⁶R¹⁷.

In one embodiment, the present invention provides a compound of formula(I) wherein R⁶ and R⁷ are independently selected from H, (C₁-C₄)alkyl,(C₁-C₄)alkoxy and (C₃-C₆)cycloalkyl.

In another embodiment, the present invention provides a compound offormula (I) wherein R⁶ is H and R⁷ is selected from (C₁-C₄)alkyl,(C₁-C₄)alkoxy and (C₃-C₆)cycloalkyl. In yet another embodiment, thepresent invention provides a compound of formula (I) wherein R⁶ is H andR⁷ is selected from methoxy (OCH₃), ethoxy (OCH₂CH₃) and(C₃-C₆)cycloalkyl.

In a yet further embodiment, the present invention provides a compoundof formula (I) wherein R⁶ is H and R⁷ is cyclopropyl.

In one embodiment, the present invention provides a compound of formula(I) wherein R¹⁶ is

In another embodiment, the present invention provides a compound offormula (I) wherein R¹⁶ is

In yet another embodiment, the present invention provides a compound offormula (I) wherein R¹⁶ is

In yet another embodiment the present invention provides a compound offormula (I) wherein R¹⁶ is

wherein R²² and R²³ each independently represent (C₁-C₆)alkyl, or R²²and R²³ together with the carbon atom to which they are attached form a(C₃-C₇)cycloalkyl ring.

In one embodiment, the present invention provides a compound of formula(I) wherein R¹⁷ is selected from H and (C₁-C₆)alkyl.

In another embodiment, the present invention provides a compound offormula (I) wherein R¹⁷ is H.

In one embodiment, the present invention provides a compound of formula(I) wherein R²² is selected from H, (C₁-C₆)alkyl, heterocycloalkyl andaryl, wherein said (C₁-C₆)alkyl may be optionally substituted with 1 or2 R²⁸ groups.

In another embodiment, the present invention provides a compound offormula (I) wherein R²² is selected from H and (C₁-C₆)alkyl; whereinsaid (C₁-C₆)alkyl may be optionally substituted with a single R²⁸ group.

In yet another embodiment, the present invention provides a compound offormula (I) wherein R²² is selected from H and branched (C₁-C₆)alkyl;wherein said branched (C₁-C₆)alkyl is substituted with a single R²⁸group.

In yet another embodiment still, the present invention provides acompound of formula (I) wherein R²² is selected from H and isopropyl;wherein said isopropyl is substituted with a single R²⁸ group.

In a further embodiment, the present invention provides a compound offormula (I) wherein R²² is selected from H and (C₁-C₆)alkyl.

In a yet further embodiment, the present invention provides a compoundof formula (I) wherein R²² is H.

In a yet further still embodiment, the present invention provides acompound of formula (I) wherein R²² is methyl.

In one embodiment, the present invention provides a compound of formula(I) wherein R²³ is H.

In another embodiment, the present invention provides a compound offormula (I) wherein R²³ is (C₁-C₆)alkyl.

In yet another embodiment, the present invention provides a compound offormula (I) wherein R²³ is methyl.

In one embodiment, the present invention provides a compound of formula(I) wherein X is a bond.

In another embodiment, the present invention provides a compound offormula (I) wherein X is a (CR²⁴R²⁵)_(n) group and n is 1.

In one embodiment, the present invention provides a compound of formula(I) wherein R²⁴ and R²⁵ are independently selected from H, OH and(C₁-C₆)alkyl.

In another embodiment, the present invention provides a compound offormula (I) wherein R²⁴ and R²⁵ are H.

In one embodiment, the present invention provides a compound of formula(I) wherein R²⁶ is selected from H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, OH,O-aryl, halo, aryl, NR³⁴R³⁵ and CONR³⁴R³⁵, wherein said (C₁-C₆)alkyl maybe optionally substituted with 1, 2, or 3 groups independently selectedfrom halo and NR³⁴R³⁵.

In another embodiment, the present invention provides a compound offormula (I) wherein R²⁶ is selected from H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,OH, halo, aryl, NR³⁴R³⁵ and CF₃.

In yet another embodiment, the present invention provides a compound offormula (I) wherein R²⁶ is selected from H, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,OH, CI and F.

In one embodiment, the present invention provides a compound of formula(I) wherein R²⁷ is H.

In one embodiment, the present invention provides a compound of formula(I) wherein each occurrence of R²⁸ is independently selected fromheterocycloalkyl, halo, CF₃, CH₂CF₃ and NR²⁹R³⁰.

In another embodiment, the present invention provides a compound offormula (I) wherein each occurrence of R²⁸ is independently selectedfrom heterocycloalkyl and NR²⁹R³⁰.

In yet another embodiment, the present invention provides a compound offormula (I) wherein R²⁸ is heterocycloalkyl.

In one embodiment, the present invention provides a compound of formula(I) wherein Z is an aryl ring substituted with R²⁶ and R²⁷.

In another embodiment, the present invention provides a compound offormula (I) wherein Z is a phenyl ring substituted with R²⁶ and R²⁷.

In one embodiment, the present invention provides a compound of formula(I) wherein heterocycloalkyl is a C-linked or N-linked 5 or 6 memberednon-aromatic, monocyclic ring, optionally fused to an aryl group,wherein said heterocycloalkyl ring contains:

one N— atom, orone N— atom and one NR⁴⁵, orone N— atom and an S(O)_(p) or an O atom,and is optionally substituted on carbon with 1 or 2 substituentsindependently selected from (C₁-C₆)alkyl, (C₁-C₆)alkoxy, OH, CN, CF₃,halo, NR⁴⁶R⁴⁷ and aryl, wherein said (C₁-C₆)alkyl may be optionallysubstituted by aryl, (C₁-C₆)alkoxy or OH; and wherein each aryl groupmay be optionally substituted with (C₁-C₆)alkoxy (which in turn may beoptionally substituted by NR³⁴R³⁵), (C₁-C₆)alkyl, OH, CF₃ and halo.

In one embodiment, the present invention provides a compound of formula(I) wherein halo is selected from CI and F.

In one embodiment, the present invention provides a compound of formula(I) wherein halo is F.

In one embodiment, the present invention provides a compound of formula(I) wherein n is 1.

In one embodiment, the present invention provides a compound of formula(I) wherein m is 0.

In one embodiment, the present invention provides a compound of formula(IA), or a pharmaceutically acceptable salt thereof

wherein:R¹ and R² are independently selected from H, (C₁-C₄)alkyl and F;R²² and R²³ are each independently selected from H and (C₁-C₆)alkyl;or R²² and R²³ together with the carbon atom to which they are bothattached form a (C₃-C₄)cycloalkyl;R²⁶ is (C₁-C₆)alkoxy which may be optionally substituted with NR³⁴R³⁵;andR³⁴ and R³⁵ are independently selected from H and (C₁-C₆)alkyl whereinsaid (C₁-C₆)alkyl may be optionally substituted by OH.

In one embodiment, the present invention provides a compound of formula(IA), wherein R¹ is selected from H and F.

In one embodiment, the present invention provides a compound of formula(IA), wherein R¹ is H.

In one embodiment, the present invention provides a compound of formula(IA), wherein R¹ is F.

In one embodiment, the present invention provides a compound of formula(IA), wherein R² is methyl.

In one embodiment, the present invention provides a compound of formula(IA) wherein R¹ is F and R² is methyl.

In one embodiment, the present invention provides a compound of formula(IA), wherein R²² and R²³ together with the carbon atom to which theyare both attached form a cyclopropyl ring.

In one embodiment, the present invention provides a compound of formula(IA), wherein R²² and R²³ each independently represent methyl or ethyl.

In one embodiment, the present invention provides a compound of formula(IA), wherein R²⁶ is (C₁-C₆)alkoxy substituted with NR³⁴R³⁵, wherein R³⁴and R³⁵ are independently selected from H and (C₁-C₄)alkyl wherein said(C₁-C₄)alkyl may be optionally substituted by OH.

In one embodiment, the present invention provides a compound of formula(IA), wherein R²⁶ is selected from

—OCH₂CH₂NH₂, —OCH₂CH₂NHCH₃, —OCH₂CH₂NHCH₂CH₃, —OCH₂CH₂NHCH(CH₃)₂,—OCH₂CH₂N(CH₂CH₃)₂, —OCH₂CH₂CH₂NHCH₃, —OCH₂CH₂CH₂CH₂NHCH₃,—OCH₂CH₂NHCH₂CH₂OH, —OCH₂CH₂N(CH₃)CH₂CH₂OH, —OCH₂CH₂NHCH(CH₃)CH₂OH,—OCH₂CH₂NHCH₂CH₂CH₂OH, and —OCH₂CH₂NHCH₂CH(OH) CH₃.

In one embodiment, the present invention provides a compound of formula(IA) selected from:

-   N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-4-methyl-3-[3-[[1-[2-[2-(methylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[(2-hydroxyethyl)amino]ethoxy]phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[[(2R)-2-hydroxypropyl]amino]ethoxy]phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[[(2S)-2-hydroxypropyl]amino]ethoxy]phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-fluoro-4-methyl-5-[3-[[1-[2-[2-(methylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[(2-hydroxyethyl)amino]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   3-[3-({1-[2-(2-Aminoethoxy)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide-   3-[3-({1-[2-(2-Aminoethoxy)phenyl]cyclopropyl}amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide-   and-   N-Cyclopropyl-3-fluoro-5-[3-{[1-(2-{2-[(2-hydroxyethyl)(methyl)amino]ethoxy}phenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide-   or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides a compound of formula(IA) selected from:

-   N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-4-methyl-3-[3-[[1-[2-[2-(methylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-3-fluoro-4-methyl-5-[3-[[1-[2-[2-(methylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide    and-   N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[(2-hydroxyethyl)amino]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides a compound of formula(ID), or a pharmaceutically acceptable salt thereof

wherein:R¹ and R² are independently selected from H, (C₁-C₄)alkyl and F;R⁶ is (C₁-C₄)alkoxy;R²² and R²³ are each independently selected from H and (C₁-C₆)alkyl;or R²² and R²³ together with the carbon atom to which they are bothattached form a (C₃-C₄)cycloalkyl;R²⁶ is (C₁-C₆)alkoxy which may be optionally substituted with NR³⁴R³⁵;andR³⁴ and R³⁵ are independently selected from H and (C₁-C₆)alkyl whereinsaid (C₁-C₆)alkyl may be optionally substituted by OH.

In one embodiment, the present invention provides a compound of formula(ID), wherein R¹ is selected from H and F.

In one embodiment, the present invention provides a compound of formula(ID), wherein R¹ is H.

In one embodiment, the present invention provides a compound of formula(ID), wherein R¹ is F.

In one embodiment, the present invention provides a compound of formula(ID), wherein R² is methyl.

In one embodiment, the present invention provides a compound of formula(ID), wherein R⁶ is methoxy.

In one embodiment, the present invention provides a compound of formula(ID), wherein R²² and R²³ together with the carbon atom to which theyare both attached form a cyclopropyl ring.

In one embodiment, the present invention provides a compound of formula(ID), wherein R²² and R²³ each independently represent methyl or ethyl.

In one embodiment, the present invention provides a compound of formula(ID), wherein R²⁶ is (C₁-C₆)alkoxy substituted with NR³⁴R³⁵, wherein R³⁴and R³⁵ are independently selected from H and (C₁-C₄)alkyl wherein said(C₁-C₄)alkyl may be optionally substituted by OH.

In one embodiment, the present invention provides a compound of formula(ID), wherein R²⁶ is —OCH₂CH₂NHCH₃.

In one embodiment, the present invention provides a compound of formula(ID) selected from:

-   3-Fluoro-N-methoxy-4-methyl-5-{3-[(1-methyl-1-{2-[2-(methylamino)ethoxy]phenyl}ethyl]amino]-2-oxopyrazin-1(2H)-yl}benzamide-   and-   N-Methoxy-4-methyl-3-{3-[(1-{2-[2-(methylamino)ethoxy]phenyl}cyclopropyl)amino]-2-oxopyrazin-1    (2H)-yl}benzamide-   or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides a compound of formula(IE), or a pharmaceutically acceptable salt thereof

wherein:R¹ and R² are independently selected from H, (C₁-C₄)alkyl and F;R⁶ is cyclopropyl or (C₁-C₄)alkoxy;R²² and R²³ are each independently selected from H and (C₁-C₆)alkyl;or R²² and R²³ together with the carbon atom to which they are bothattached form a (C₃-C₄)cycloalkyl; andR³⁴ and R³⁵ are independently selected from H and (C₁-C₆)alkyl whereinsaid (C₁-C₆)alkyl may be optionally substituted by OH.

In one embodiment, the present invention provides a compound of formula(IE), wherein R¹ is selected from H and F.

In one embodiment, the present invention provides a compound of formula(IE), wherein R¹ is H.

In one embodiment, the present invention provides a compound of formula(IE), wherein R¹ is F.

In one embodiment, the present invention provides a compound of formula(IE), wherein R² is methyl.

In one embodiment, the present invention provides a compound of formula(IE), wherein R⁶ is cyclopropyl.

In one embodiment, the present invention provides a compound of formula(IE), wherein R²² and R²³ together with the carbon atom to which theyare both attached form a cyclopropyl ring.

In one embodiment, the present invention provides a compound of formula(IE), wherein R²² and R²³ each independently represent methyl or ethyl.

In one embodiment, the present invention provides a compound of formula(IE), wherein R³⁴ and R³⁵ are independently selected from H and(C₁-C₄)alkyl.

In one embodiment, the present invention provides a compound of formula(IE) selected from:

-   N-Cyclopropyl-3-fluoro-5-[3-{[1-(2-{[(2R)-2-hydroxy-3-(methylamino)propyl]oxy}phenyl)-1-methylethyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide-   N-Cyclopropyl-3-[3-{[1-(2-{[(2R)-3-(ethylamino)-2-hydroxypropyl]oxy}phenyl)-1-methylethyl]amino}-2-oxopyrazin-1(2H)-yl]-5-fluoro-4-methylbenzamide-   and-   N-Cyclopropyl-3-fluoro-5-[3-{[1-(2-{[(2S)-2-hydroxy-3-(methylamino)propyl]oxy}phenyl)-1-methylethyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide    or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides a compound of formula(I) selected from:

-   N-methoxy-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-(4-morpholinyl)-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide;-   N-methoxy-4-methyl-3-[2-oxo-3-[[(1R)-1-phenylpropyl]amino]-1(2H)-pyrazinyl]-benzamide;-   N-methoxy-4-methyl-3-[3-[[(1R,2S)-2-methyl-1-phenyl-3-(1-pyrrolidinyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide;-   N-cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide;-   N-cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[3-(methylamino)propoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide;-   N-cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(1-pyrrolidinyl)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide;-   N-methoxy-4-methyl-3-[3-[(1-methyl-1-phenylethyl)amino]-2-oxo-1(2H)-pyrazinyl]-benzamide;-   3-[3-[[(1R,2R)-3-hydroxy-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-methoxy-4-methyl-benzamide;-   N-cyclopropyl-4-methyl-3-[2-oxo-3-[[(1R)-1-[2-[2-(1-pyrrolidinyl)ethoxy]phenyl]propyl]amino]-1(2H)-pyrazinyl]-benzamide;-   N-cyclopropyl-3-[3-[[(1R,2S)-3-[(1,1-dimethylethyl)amino]-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide;-   N-methoxy-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-(4-morpholinyl)-1-(1-naphthalenyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide;-   N-cyclopropyl-3-[3-[[(1R,2S)-3-[[2-(dimethylamino)ethyl]amino]-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide;-   N-cyclopropyl-3-[3-[[(1R,2S)-3-[4-(hydroxymethyl)-1-piperidinyl]-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide;-   N-methoxy-4-methyl-3-[3-[[(1R,2S)-2-methyl-1-(1-naphthalenyl)-3-(1-pyrrolidinyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide;-   N-cyclopropyl-3-[3-[[(1R,2S)-3-[(2,2-dimethyl    propyl)amino]-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide;-   N-cyclopropyl-3-[3-[[(1R,2S)-3-[(1,1-dimethylethyl)methylamino]-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide;-   N-cyclopropyl-3-[3-[[(1R,2S)-3-[(2R)-2-(methoxymethyl)-1-pyrrolidinyl]-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide;-   N-cyclopropyl-3-[3-[[(1R,2S)-3-[(2S)-2-(methoxymethyl)-1-pyrrolidinyl]-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide;-   N-cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-(4-morpholinyl)-1-phenyl    propyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide;-   N-cyclopropyl-4-methyl-3-[2-oxo-3-[[(1R)-1-phenylpropyl]amino]-1(2H)-pyrazinyl]-benzamide;-   N-cyclopropyl-3-[3-[[(1R,2S)-3-(4-hydroxy-1-piperidinyl)-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide;-   N-cyclopropyl-3-[3-[[(1R,2S)-3-(diethylamino)-2-methyl-1-phenyl    propyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide;-   N-cyclopropyl-3-[3-[[(1R,2S)-3-[[2-(dimethylamino)ethyl]methylamino]-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide;-   N-cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-1-phenyl-3-(1-piperidinyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide;-   N-cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-1-phenyl-3-(1-pyrrol    idinyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide;-   N-cyclopropyl-3-[3-[[(1R,2S)-3-(dimethylamino)-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide;-   N-cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-(4-methyl-1-piperazinyl)-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide;-   3-[3-[[(1R,2S)-3-(4-acetyl-1-piperazinyl)-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide;-   N-cyclopropyl-3-[3-[[1-(2-hydroxyphenyl)-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide;-   N-cyclopropyl-4-methyl-3-[3-[2-(3-methylphenyl)-1-pyrrolidinyl]-2-oxo-1(2H)-pyrazinyl]-benzamide;-   N-cyclopropyl-3-[3-[2-(2-methoxyphenyl)-1-pyrrolidinyl]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide;-   N-cyclopropyl-4-methyl-3-[3-[[1-[2-[2-(methylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide;-   N-cyclopropyl-4-methyl-3-[3-[[1-[2-[2-(ethylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide;    and-   N-cyclopropyl-3-fluoro-4-methyl-5-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide,-   N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-(4-methyl-1-piperidinyl)-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-[4-(1-methylethyl)-1-piperazinyl]-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-1-phenyl-3-(1-piperazinyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-3-[3-[[(1R,2S)-3-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-[3-[[(1R,2S)-3-(4-fluoro-1-piperidinyl)-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-[3-[[(1R,2S)-3-(4,4-difluoro-1-piperidinyl)-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-[3-[[(1R,2S)-3-[4-(dimethylamino)-1-piperidinyl]-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-4-methy-3-[3-[[(1R,2S)-2-methyl-1-phenyl-3-[4-(trifluoromethyl)-1-piperidinyl]propyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-4-methy-3-[3-[[(1R,2S)-2-methyl-3-(3-oxo-1-piperazinyl)-1-phenylpropyl]amino]-2-oxo-1    (2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-3-[3-[[(1R,2S)-3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-[(3R)-3-methyl-1-piperazinyl]-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-[(3S)-3-methyl-1-piperazinyl]-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-[(2-methylpropyl)amino]-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-3-[3-[(1R,2S)-3-(cyclopropylamino)-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-[(2R)-2-methyl-1-pyrrolidinyl]-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-3-[3-[[(1R,2S)-3-[(3S)-3-hydroxy-1-piperidinyl]-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-[3-[[(1R,2S)-3-[(3R)-3-hydroxy-1-piperidinyl]-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-[(2R)-2-methyl-1-piperazinyl]-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-3-[3-[[(1R,2S)-3-(2,7-diazaspiro[3.5]non-7-yl)-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-1-phenyl-3-(4-thiomorpholinyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-3-[3-[[(1R,2S)-3-[(3S)-3-hydroxy-1-pyrrolidinyl]-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-1-phenyl-3-[4-(tetrahydro-1,1-dioxido-3-thienyl)-1-piperazinyl]propyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   1-[(2S,3R)-3-[[4-[5-[(cyclopropylamino)carbonyl]-2-methylphenyl]-3,4-dihydro-3-oxopyrazinyl]amino]-2-methyl-3-phenylpropyl]-4-piperidinecarboxamide-   N-Cyclopropyl-3-[3-[[(1R,2S)-3-[(2-hydroxy-1,1-di    methylethyl]amino]-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-[3-[[(1R,2S)-3-[(3R,5S)-3,5-dimethyl-1-piperazinyl]-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-1-phenyl-3-(4-piperidinylamino)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-(5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-3-[3-[[(1R,2S)-3-(2,2-dimethyl-1-pyrrolidinyl)-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-[3-[[1-[2-[2-(ethylamino)ethoxy]phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide.-   N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(1-piperazinyl)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-3-[3-[[1-[2-[2-(di    ethylamino)ethoxy]phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(1-piperidinyl)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(4-methyl-1-piperazinyl)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(4-morpholinyl)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[4-(methylamino)butoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[4-[(2,2,2-trifluoroethyl)amino]butoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[4-(4-methyl-1-piperazinyl)butoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[3-[(2,2,2-trifluoroethyl)amino]propoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[3-(4-methyl-1-piperazinyl)propoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[1-methyl-2-(4-methyl-1-piperazinyl)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-3-[3-[[1-[2-[2-[(2-methoxyethyl)amino]ethoxy]phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-[3-[[1-[2-[2-[(2-hydroxyethyl)amino]ethoxy]phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-[(1-methylethyl)amino]ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-3-[3-[[1-[2-[2-[[(2S)-2-hydroxypropyl]amino]ethoxy]phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-6-benzamide-   N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-(4-piperidinylmethoxy)phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-4-methyl-3-[3-[[1-[2-(3-azetidinyloxy)phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-(3-pyrrolidinyloxy)phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(4-piperidinyl)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-(3-piperidinylmethoxy)phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-(4-piperidinyloxy)phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Ethoxy-4-methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   4-Methyl-N-(1-methylcyclopropyl)-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   4-Methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-3-[3-[[1-[2-[2-[[(2S)-2-hydroxypropyl]amino]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-[3-[[1-[2-[2-[(2-methoxyethyl)amino]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-[3-[[1-[2-[2-[4-(2-hydroxyethyl)-1-piperazinyl]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-[3-[[1-[2-[2-[(2-hydroxyethyl)amino]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-4-methyl-3-[3-[[1-[2-[2-[(1-methylethyl)amino]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-3-[3-[[1-[2-[2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-[3-[[1-[2-[2-[(3R)-3-hydroxy-1-pyrrolidinyl]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-[3-[[1-[2-[2-(dimethylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-4-methyl-3-[2-oxo-3-[[1-[2-[2-(1-pyrrolidinyl)ethoxy]phenyl]cyclopropyl]amino]-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-3-[3-[[1-[2-[2-[(2S)-2-(hydroxymethyl)-1-pyrrolidinyl]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-4-methyl-3-[2-oxo-3-[[1-[2-[2-[(2,2,2-trifluoroethyl)amino]ethoxy]phenyl]cyclopropyl]amino]-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-3-[3-[[1-[2-[2-(ethylmethylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-[3-[[1-[2-[2-[(3-hydroxy-2,2-dimethylpropyl)amino]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-4-methyl-3-[2-oxo-3-[[1-[2-[2-(1-piperazinyl)ethoxy]phenyl]cyclopropyl]amino]-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-3-[3-[[1-[2-[2-(3,3-difluoro-1-pyrrolidinyl)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-[3-[[1-[2-[2-[(2-fluoroethyl)amino]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-4-methyl-3-[3-[[1-[2-[2-[(1-methylpropyl)amino]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-4-methyl-3-[3-[[1-[2-[2-[(2R)-2-methyl-1-pyrrolidinyl]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   3-[3-[[1-[2-[2-(cyclobutylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-Cyclopropyl-4-methyl-benzamide-   N-Cyclopropyl-3-[3-[[1-[2-[2-[[(1R)-2-hydroxy-1-methylethyl]amino]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-[3-[[1-[2-[2-[(3-hydroxypropyl)amino]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   3-[3-[[1-[2-(2-aminoethoxy)phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide-   N-Cyclopropyl-3-[3-[[1-[2-[2-(ethylamino)ethoxy]phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-5-fluoro-4-methyl-benzamide-   N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[(2-hydroxyethyl)amino]ethoxy]phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-fluoro-4-methyl-5-[3-[[1-methyl-1-[2-[2-[(1-methylethyl)amino]ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benamide-   N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[(2-methoxyethyl)amino]ethoxy]phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[[(2R)-2-hydroxypropyl]amino]ethoxy]phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[(2-hydroxy-2-methylpropyl)amino]ethoxy]phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[[(2S)-2-hydroxypropyl]amino]ethoxy]phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-fluoro-4-methyl-5-[3-[[1-[2-[2-(methylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[(2-hydroxyethyl)amino]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[(2-methoxyethyl)amino]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-[3-[[1-[2-[2-(ethylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-5-fluoro-4-methyl-benzamide-   N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[[(2S)-2-hydroxypropyl]amino]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-fluoro-4-methyl-5-[3-[[1-[2-[2[(1-methylethyl)amino]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[[(2R)-2-hydroxypropyl]amino]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-[3-[[1-[2-[2-(ethylamino)ethoxy]phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-[3-[[1-ethyl-1-[2-[2-(ethylamino)ethoxy]phenyl]propyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-4-methyl-3-[3-[1-[2-[2-(methylamino)ethoxy]phenyl]cyclobutyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-3-[3-[[1-[2-[2-(ethylamino)ethoxy]phenyl]cyclobutyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-[3-[[1-[2-[2-[(2-hydroxyethyl)amino]ethoxy]phenyl]cyclobutyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-4-methyl-3-[3-[[1-[2-[2[(1-methylethyl]amino]ethoxy]phenyl]cyclobutyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide-   N-Cyclopropyl-3-[3-[[(1R,2R)-3-hydroxy-1-(2-methylphenyl)-2-methylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-[3-[[(1R,2R)-3-hydroxy-1-(3-methylphenyl)-2-methylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-[3-[[(1R,2R)-3-hydroxy-1-(2-methoxyphenyl)-2-methylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-[3-[[(1R,2S)-1-(2-methylphenyl)-2-methyl-3-(1-pyrrolidinyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-[3-[[(1R,2S)-1-(3-methylphenyl)-2-methyl-3-(1-pyrrolidinyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-[3-[[(1R,2S)-1-(2-methoxyphenyl)-2-methyl-3-(1-pyrrolidinyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-[3-[[1-[5-fluoro-2-[2-(methylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-[3-[[1-[5-fluoro-2-[2-[(2-hydroxyethyl)amino]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-[3-[[1-[2-[2-(ethylamino)ethoxy]-5-fluorophenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide-   N-Cyclopropyl-3-fluoro-5-{3-[(1-{5-fluoro-2-[2-(methylamino)ethoxy]phenyl}cyclopropyl)amino]-2-oxopyrazin-1(2H)-yl}-4-methylbenzamide-   N-Cyclopropyl-3-fluoro-5-[3-{[1-(5-fluoro-2-{2-[(2-hydroxyethyl)amino]ethoxy}phenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide-   N-Cyclopropyl-3-[3-({1-[3-fluoro-2-(2-{[(2R)-2-hydroxypropyl]amino}ethoxy)phenyl]cyclopropyl}amino)-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide-   3-[3-({1-[2-(2-Aminoethoxy)-3-fluorophenyl]cyclopropyl}amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-4-methylbenzamide-   N-Cyclopropyl-3-[3-{[1-(3-fluoro-2-{2-[(2-hydroxyethyl)amino]ethoxy}phenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide-   N-Cyclopropyl-3-{3-[(1-{2-[2-(ethylamino)ethoxy]-3-fluorophenyl}cyclopropyl)amino]-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide-   N-Cyclopropyl-3-{3-[(1-{3-fluoro-2-[2-(methylamino)ethoxy]phenyl}cyclopropyl)amino]-2-oxopyrazin-1(2H)-yl}-4-methylbenzamide-   N-Cyclopropyl-4-ethyl-3-[3-({1-[2-(2-{[(2S)-2-hydroxypropyl]amino]ethoxy)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1(2H)-yl]benzamide-   N-Cyclopropyl-4-ethyl-3-{3-[(1-{2-[2-(ethylamino)ethoxy]phenyl}-1-methyl    ethyl)amino]-2-oxopyrazin-1(2H)-yl}benzamide-   N-Cyclopropyl-3-[3-({1-[2-(2-{[(1R)-1-(hydroxymethyl)-2-methylpropyl]amino]ethoxy)phenyl]cyclopropyl}amino)-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide-   N-Cyclopropyl-3-[3-({1-[2-(2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}ethoxy)phenyl]cyclopropyl]amino)-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide-   N-Cyclopropyl-3-[3-{[1-(2-{2-[(1,1-dioxidotetrahydrothiophen-3-yl)amino]ethoxy}phenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide-   N-Cyclopropyl-3-{3-[(1-{2-[2-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethoxy]phenyl}cyclopropyl)amino]-2-oxopyrazin-1(2H)-yl}-4-methylbenzamide-   N-Cyclopropyl-4-methyl-3-{3-[(1-{2-[2-(1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethoxy]phenyl}cyclopropyl)amino]-2-oxopyrazin-1(2H)-yl}benzamide-   N-Cyclopropyl-4-methyl-3-{2-oxo-3-[(1-{2-[2-(propylamino)ethoxy]phenyl}cyclopropyl)amino]pyrazin-1(2H)-yl}benzamide-   N-Cyclopropyl-3-[3-({1-[2-({(2R)-2-hydroxy-3-[(2-hydroxyethyl)amino]propyl}oxy)phenyl]cyclopropyl]amino)-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide-   N-Cyclopropyl-3-[3-{[1-(2-{[(2R)-3-(ethylamino)-2-hydroxypropyl]oxy}phenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide-   N-Cyclopropyl-3-[3-{[1-(2-{[(2R)-2-hydroxy-3-(methylamino)propyl]oxy}phenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide-   N-Cyclopropyl-3-[3-({1-[2-({(2S)-2-hydroxy-3-[(2-hydroxyethyl)amino]propyl}oxy)phenyl]cyclopropyl]amino)-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide-   N-cyclopropyl-3-[3-{{1-(2-{[(2S)-3-(ethylamino)-2-hydroxypropyl]oxy}phenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide-   N-Cyclopropyl-3-[3-{[1-(2-{[(2S)-2-hydroxy-3-(methylamino)propyl]oxy}phenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide-   3-[3-{[1-(2-{[(2R)-2-Amino-3-hydroxypropyl]oxy}phenyl)-1-methylethyl]amino}-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-4-methylbenzamide-   N-Cyclopropyl-3-[3-{[1-(2-{[(2R)-2-(dimethylamino)-3-hydroxypropyl]oxy}phenyl)-1-methylethyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide-   N-Cyclopropyl-3-fluoro-5-[3-{[1-(2-{[(2R)-2-hydroxy-3-(methylamino)propyl]oxy}phenyl)-1-methylethyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide-   N-Cyclopropyl-3-[3-{[1-(2-{[(2R)-3-(ethylamino)-2-hydroxypropyl]oxy}phenyl)-1-methylethyl]amino]-2-oxopyrazin-1(2H)-yl]-5-fluoro-4-methylbenzamide-   N-Cyclopropyl-3-[3-{[1-(2-{[(2S)-3-(ethylamino)-2-hydroxypropyl]oxy}phenyl)-1-methylethyl]amino}-2-oxopyrazin-1(2H)-yl]-5-fluoro-4-methylbenzamide-   N-Cyclopropyl-3-fluoro-5-[3-{[1-(2-{[(2S)-2-hydroxy-3-(methylamino)propyl]oxy}phenyl)-1-methylethyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide-   3-[3-({1-[2-(2-Aminoethoxy)phenyl]-1-methylethyl]amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide-   N-(2-{2-[1-({4-[5-(Cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-3-oxo-3,4-dihydropyrazin-2-yl]amino)-1-methylethyl]phenoxy}ethyl)glycine-   N-(2-{2-[1-({4-[5-(Cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-3-oxo-3,4-dihydropyrazin-2-yl}amino)-1-methylethyl]phenoxy}ethyl)-beta-alanine-   3-[3-({1-[2-(2-Aminoethoxy)phenyl]cyclopropyl}amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide-   N-Cyclopropyl-3-fluoro-5-[3-{[1-(2-{2-[(2-hydroxyethyl)(methyl)amino]ethoxy}phenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide-   3-Fluoro-N-methoxy-4-methyl-5-{3-[(1-methyl-1-{2-[2-(methylamino)ethoxy]phenyl}ethyl]amino]-2-oxopyrazin-1(2H)-yl}benzamide-   N-Methoxy-4-methyl-3-{3-[(1-{2-[2-(methylamino)ethoxy]phenyl}cyclopropyl)amino]-2-oxopyrazin-1(2H)-yl}benzamide-   N-Cyclopropyl-3-fluoro-4-methyl-5-[3-{[1-methyl-1-(2-{[2-(methylamino)ethyl]sulfanyl}phenyl)ethyl]amino}-2-oxopyrazin-1(2H)-yl]benzamide-   3-{3-[(1-{2-[(2-Aminoethyl)sulfanyl]phenyl}-1-methylethyl)amino]-2-oxopyrazin-1(2H)-yl}-N-cyclopropyl-5-fluoro-4-methylbenzamide-   N-Cyclopropyl-3-fluoro-4-methyl-5-{3-[(1-methyl-1-{2-[3-(methylamino)propyl]phenyl}ethyl)amino]-2-oxopyrazin-1(2H)-yl}benzamide-   N-Cyclopropyl-4-methyl-3-[3-(2-{2-[3-(methylamino)propoxy]phenyl}pyrrolidin-1-yl)-2-oxopyrazin-1(2H)-yl]benzamide-   N-Cyclopropyl-3-fluoro-4-methyl-5-[3-{[(1R,2S)-2-methyl-1-phenyl-3-pyrrolidin-1-ylpropyl]amino}-2-oxopyrazin-1(2H)-yl]benzamide-   N-Cyclopropyl-3-fluoro-4-methyl-5-[3-{[(1R,2S)-2-methyl-1-phenyl-3-piperidin-1-ylpropyl]amino}-2-oxopyrazin-1(2H)-yl}benzamide-   4-Chloro-N-cyclopropyl-3-[3-[(1-methyl-1-{2-[2-(methylamino)ethoxy]phenyl}ethyl)amino]-2-oxopyrazin-1(2H)-yl]benzamide-   4-Chloro-N-cyclopropyl-3-[3-{[1-(2-{2-[(2-hydroxyethyl)amino]ethoxy}phenyl)-1-methylethyl]amino}-2-oxopyrazin-1(2H)-yl]benzamide-   4-Chloro-N-cyclopropyl-3-[3-({1-[2-(2-{[(2R)-2-hydroxypropyl]amino}ethoxy)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1(2H)-yl]benzamide-   4-Chloro-N-cyclopropyl-3-[3-[(1-{2-[2-(ethylamino)ethoxy]phenyl}-1-m    ethylethyl)amino]-2-oxopyrazin-1(2H)-yl]benzamide-   3-[3-({1-[2-(2-Aminoethoxy)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1(2H)-yl]-4-chloro-N-cyclopropylbenzamide-   or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides compounds of formula(IB):

wherein:R¹ and R² are independently selected from H, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo, CF₃, and CN;R³ and R⁴ are independently selected from H, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo, OH, NR⁸R⁹, CF₃, CN, aryl, heteroaryl and CONR¹⁰R¹¹,wherein said (C₁-C₆)alkyl and said (C₁-C₆)alkoxy are, independently,optionally substituted with 1, 2 or 3 groups independently selected fromOH, (C₁-C₃)alkoxy, NR¹²R¹³, S(O)_(p)R⁵⁵ and halo;R⁵ is selected from H, aryl, heteroaryl, heterocycloalkyl,(C₃-C₇)cycloalkyl, (CR¹⁴R¹⁵)_(m)NR¹⁶R¹⁷, S(O)_(p)R¹⁶, SO₂NR¹⁶R¹⁷, CH₂R¹⁶and OR¹⁶;R⁶ is selected from H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₇)cycloalkyl,heteroaryl and aryl;R⁷ is selected from H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₇)cycloalkyland aryl;

or R⁶ and R⁷ together with the nitrogen atom to which they are attachedform a 4 to 7 membered ring, optionally containing a further heteroatomselected from NR¹⁸, S and O;

R⁸ and R⁹ are independently selected from H, (C₁-C₆)alkyl, (C₁-C₆)alkoxyand (C₃-C₆)cycloalkyl; or R⁸ and R⁹ together with the nitrogen atom towhich they are attached form a 4 to 7 membered ring, optionallycontaining a further heteroatom selected from NR¹⁹, S and O;R¹⁴ and R¹⁵ are selected from H and (C₁-C₆)alkyl; or R¹⁴ and R¹⁵together with the carbon to which they are attached form a carbonyl(C═O) group;R¹⁶ is selected from H, aryl, (C₃-C₇)cycloalkyl and

wherein said (C₃-C₇)cycloalkyl may be optionally substituted with anaryl group;R¹⁷ is selected from H, (C₁-C₆)alkyl, aryl, heteroaryl, heterocycloalkyland (C₃-C₇)cycloalkyl, wherein said (C₁-C₆)alkyl may be optionallysubstituted with 1, 2 or 3 groups independently selected from(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, heteroaryl andNR²⁰R²¹;R²² is selected from H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, OH, NR²⁹R³⁰,heterocycloalkyl and aryl, wherein said (C₁-C₆)alkyl may be optionallysubstituted with 1, 2 or 3 R²⁸ groups; and wherein said aryl may beoptionally substituted with 1, 2 or 3 groups independently selected from(C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo, CF₃ and OH;R²³ is selected from H and (C₁-C₆)alkyl;or R²² and R²³ together with the carbon atom to which they are attachedform a (C₃-C₇)cycloalkyl or heterocycloalkyl ring;X is a bond or a (CR²⁴R²⁵)_(n) group;R²⁴ and R²⁵ are independently selected from H, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, OH, heterocycloalkyl and NR³⁹R⁴⁰; or R²⁴ and R²⁵ togetherwith the carbon atom to which they are attached may form aheterocycloalkyl ring;Z is an aryl or heteroaryl ring, wherein said aryl or heteroaryl ring issubstituted with R²⁶ and R²⁷;

R²⁶ is selected from H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, OH, aryl, O-aryl,halo, heterocycloalkyl, O-heterocycloalkyl, heteroaryl, O-heteroaryl,cycloalkyl, O-cycloalkyl, S(O)_(p)R³⁴, NR³⁴R³⁵ and CONR³⁴R³⁵, whereinsaid (C₁-C₆)alkyl or said (C₁-C₆)alkoxy may be optionally substitutedwith 1, 2 or 3 groups independently selected from halo, heterocycloalkylor NR³⁴R³⁵;

R²⁷ is selected from H, halo and (C₁-C₆)alkyl, wherein said (C₁-C₆)alkylmay be optionally substituted with 1, 2 or 3 halo groups;or R²⁶ and R²⁷ together may form a methylenedioxy group, when attachedto adjacent carbon atoms of the aryl or heteroaryl ring;each occurrence of R²⁸ is independently selected from NR²⁹R³⁰, halo,CH₂CF₃, CF₃, heterocycloalkyl, (C₁-C₆)alkoxy, OR³⁶, COOR⁴², CONR³¹R³²and SO₂NR³⁷R³⁸;R²⁹ and R³⁰ are independently selected from H, (C₁-C₆)alkyl, SO₂R⁴¹ andC(O)R⁴¹, wherein said (C₁-C₆)alkyl may be optionally substituted withNR⁵⁶R⁵⁷ or heterocycloalkyl;R³¹ and R³² are independently selected from H, (C₁-C₆)alkyl and(C₃-C₇)cycloalkyl; or R³¹ and R³² together with the nitrogen atom towhich they are attached form a 4 to 7 membered ring, optionallycontaining a further heteroatom selected from NR³³, S and O;R³⁴ and R³⁵ are independently selected from H, (C₁-C₆)alkyl,(C₃-C₇)cycloalkyl and C(O)O(C₁-C₆)alkyl, wherein said (C₁-C₆)alkyl maybe optionally substituted by OH, halo, (C₁-C₆)alkoxy, NR⁵⁸R⁵⁹ andheterocycloalkyl; or R³⁴ and R³⁵ together with the nitrogen to whichthey are attached form a 4 to 7 membered ring;R³⁶ is selected from H, (C₁-C₆)alkyl and heterocycloalkyl, wherein said(C₁-C₆)alkyl may be optionally substituted with heterocycloalkyl;R¹⁰, R¹¹, R¹², R¹³, R¹⁸, R¹⁹, R²⁰, R²¹, R³³, R³⁷, R³⁸, R³⁹, R⁴⁰, R⁴¹ andR⁴² are independently selected from H and (C₁-C₆)alkyl;

M is 0 or 1;

n is 1 or 2;each occurrence of p is independently selected from 0, 1 or 2;cycloalkyl is a non-aromatic carbocyclic ring, optionally fused to anaryl group, wherein said cycloalkyl ring optionally contains, wherepossible, up to 2 double bonds; andwherein, unless otherwise stated, said cycloalkyl may be optionallysubstituted with 1 or 2 substituents independently selected from(C₁-C₆)alkyl, (C₁-C₆)alkoxy, OH, CN, CF₃, halo and NR⁴³R⁴⁴;heterocycloalkyl is a C-linked or N-linked 3 to 9 membered non-aromatic,mono- or bi-cyclic ring, optionally fused to an aryl group, wherein saidheterocycloalkyl ring contains:1 or 2 NR⁴⁵ atoms, orone N— atom, orone N— atom and one NR⁴⁵, orone N— atom, one NR⁴⁵ and an S(O)_(p) or an O atom, orone N— atom and an S(O)_(p) or an O atom, orone S atom, orone O atom;optionally containing, where possible, 1 or 2 double bonds; andoptionally substituted on carbon with 1 or 2 substituents independentlyselected from (C₁-C₆)alkyl, (C₁-C₆)alkoxy, OH, CN, CF₃, halo, NR⁴⁶R⁴⁷and aryl, wherein said (C₁-C₆)alkyl may be optionally substituted byaryl, (C₁-C₆)alkoxy or OH; and wherein each aryl group may be optionallysubstituted with (C₁-C₆)alkoxy (which in turn may be optionallysubstituted by NR³⁴R³⁵), (C₁-C₆)alkyl, OH, CF₃ and halo;aryl is an aromatic ring containing 6 or 10 carbon atoms; wherein,unless otherwise stated, said aryl may be optionally substituted with 1,2 or 3 substituents independently selected from (C₁-C₆)alkyl,(C₁-C₆)alkoxy, OH, halo, CN, CF₃ and NR⁴⁸R⁴⁹;heteroaryl is a 5, 6, 9 or 10 membered aromatic ring, containing from 1or 2 N atoms and, optionally, an NR⁵⁰ atom, or one NR⁵⁰ atom and an S oran O atom, or one S atom, or one O atom; wherein, unless otherwisestated, said heteroaryl may be optionally substituted with 1, 2 or 3substituents independently selected from (C₁-C₆)alkyl, (C₁-C₆)alkoxy,OH, halo, CN, CF₃ and NR⁵¹R⁵²;R⁴⁵ is selected from H, (C₁-C₆)alkyl, C(O)(C₁-C₆)alkyl,C(O)O(C₁-C₆)alkyl and aryl, wherein said (C₁-C₆)alkyl is optionallysubstituted with a group selected from (C₁-C₃)alkoxy, OH, halo,heterocycloalkyl and NR²⁹R³⁰; and wherein said C(O)O(C₁-C₆)alkyl isoptionally substituted with an aryl group;R⁵⁰ is selected from H, (C₁-C₆)alkyl and C(O)O(C₁-C₆)alkyl, wherein said(C₁-C₆)alkyl may be optionally substituted with a group selected from(C₁-C₃)alkoxy, OH, halo, (C₃-C₆)cycloalkyl and NR⁵³R⁵⁴;R⁴³, R⁴⁴, R⁴⁶, R⁴⁷, R⁴⁸, R⁴⁹, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷R⁵⁸ andR⁵⁹ are each independently selected from H and (C₁-C₆)alkyl;or pharmaceutically acceptable salts thereof.

For compounds of formula (IB), embodiments of the invention includethose wherein each of R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are as definedherein above in embodiments of the invention concerning compounds offormula (I).

In one embodiment, the present invention provides a compound of formula(IC):

wherein:R¹ and R² are independently selected from H, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo, CF₃, and CN;R³ and R⁴ are independently selected from H, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo, OH, NR⁸R⁹, CF₃, CN, aryl, heteroaryl and CONR¹⁰R¹¹,wherein said (C₁-C₆)alkyl and said (C₁-C₆)alkoxy are, independently,optionally substituted with 1, 2 or 3 groups independently selected fromOH, (C₁-C₃)alkoxy, NR¹²R¹³, S(O)_(p)R⁵⁵ and halo;R⁵ is selected from H, aryl, heteroaryl, heterocycloalkyl,(C₃-C₇)cycloalkyl, (CR¹⁴R¹⁵)_(m)NR¹⁶R¹⁷, S(O)_(p)R¹⁶, SO₂NR¹⁶R¹⁷, CH₂R¹⁶and OR¹⁶;R⁶ is selected from H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₇)cycloalkyl,—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl, heteroaryl and aryl; wherein said(C₁-C₆)alkyl may be optionally substituted by halo or OH;R⁷ is selected from H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₇)cycloalkyland aryl;or R⁶ and R⁷ together with the nitrogen atom to which they are attachedform a 4 to 7 membered ring, optionally containing a further heteroatomselected from NR¹⁸, S and O;R⁸ and R⁹ are independently selected from H, (C₁-C₆)alkyl, (C₁-C₆)alkoxyand (C₃-C₆)cycloalkyl; or R⁸ and R⁹ together with the nitrogen atom towhich they are attached form a 4 to 7 membered ring, optionallycontaining a further heteroatom selected from NR¹⁹, S and O;R¹⁴ and R¹⁵ are selected from H and (C₁-C₆)alkyl; or R¹⁴ and R¹⁵together with the carbon to which they are attached form a carbonyl(C═O) group;R¹⁶ is selected from H, aryl, (C₃-C₇)cycloalkyl and

wherein said (C₃-C₇)cycloalkyl may be optionally substituted with anaryl group;R¹⁷ is selected from H, (C₁-C₆)alkyl, aryl, heteroaryl, heterocycloalkyland (C₃-C₇)cycloalkyl, wherein said (C₁-C₆)alkyl may be optionallysubstituted with 1, 2 or 3 groups independently selected from(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, heteroaryl andNR²⁰R²¹;R²² is selected from H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, OH, NR²⁹R³⁰,heterocycloalkyl and aryl, wherein said (C₁-C₆)alkyl may be optionallysubstituted with 1, 2 or 3 R²⁸ groups; and wherein said aryl may beoptionally substituted with 1, 2 or 3 groups independently selected from(C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo, CF₃ and OH;R²³ is selected from H and (C₁-C₆)alkyl;or R²² and R²³ together with the carbon atom to which they are attachedform a (C₃-C₇)cycloalkyl or heterocycloalkyl ring;X is a bond or a (CR²⁴R²⁵)_(n) group;R²⁴ and R²⁵ are independently selected from H, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, OH, heterocycloalkyl and NR³⁹R⁴⁰; or R²⁴ and R²⁵ togetherwith the carbon atom to which they are attached may form aheterocycloalkyl ring;Z is an aryl or heteroaryl ring, wherein said aryl or heteroaryl ring issubstituted with R²⁶ and R²⁷;R²⁶ is selected from H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, OH, aryl, O-aryl,halo, heterocycloalkyl, O-heterocycloalkyl, heteroaryl, O-heteroaryl,cycloalkyl, O-cycloalkyl, S(O)_(p)R³⁴, NR³⁴R³⁵ and CONR³⁴R³⁵, whereinsaid (C₁-C₆)alkyl or said (C₁-C₆)alkoxy may be optionally substitutedwith 1, 2 or 3 groups independently selected from halo, heterocycloalkylor NR³⁴R³⁵;R²⁷ is selected from H, halo and (C₁-C₆)alkyl, wherein said (C₁-C₆)alkylmay be optionally substituted with 1, 2 or 3 halo groups;or R²⁶ and R²⁷ together may form a methylenedioxy group, when attachedto adjacent carbon atoms of the aryl or heteroaryl ring;each occurrence of R²⁸ is independently selected from NR²⁹R³⁰, halo,CH₂CF₃, CF₃, heterocycloalkyl, (C₁-C₆)alkoxy, OR³⁶, COOR⁴², CONR³¹R³²and SO₂NR³⁷R³⁸;R²⁹ and R³⁰ are independently selected from H, (C₁-C₆)alkyl,(C₃-C₇)cycloalkyl, SO₂R⁴¹ and C(O)R⁴¹, wherein said (C₁-C₆)alkyl may beoptionally substituted with, OH, NR⁵⁶R⁵⁷ or heterocycloalkyl;R³¹ and R³² are independently selected from H, (C₁-C₆)alkyl and(C₃-C₇)cycloalkyl; or R³¹ and R³² together with the nitrogen atom towhich they are attached form a 4 to 7 membered ring, optionallycontaining a further heteroatom selected from NR³³, S and O;R³⁴ and R³⁵ are independently selected from H, (C₁-C₆)alkyl,(C₃-C₇)cycloalkyl and C(O)O(C₁-C₆)alkyl, wherein said (C₁-C₆)alkyl maybe optionally substituted by OH, halo, (C₁-C₆)alkoxy, NR⁵⁸R⁵⁹ andheterocycloalkyl; or R³⁴ and R³⁵ together with the nitrogen to whichthey are attached form a 4 to 7 membered ring;R³⁶ is selected from H, (C₁-C₆)alkyl and heterocycloalkyl, wherein said(C₁-C₆)alkyl may be optionally substituted with heterocycloalkyl;R¹⁰, R¹¹, R¹², R¹³, R¹⁸, R¹⁹, R²⁰, R²¹, R³³, R³⁷, R³⁸, R³⁹, R⁴⁰, R⁴¹ andR⁴² are independently selected from H and (C₁-C₆)alkyl;m is 0 or 1;n is 1 or 2;each occurrence of p is independently selected from 0, 1 or 2;cycloalkyl is a non-aromatic carbocyclic ring, optionally fused to anaryl group, wherein said cycloalkyl ring optionally contains, wherepossible, up to 2 double bonds; andwherein, unless otherwise stated, said cycloalkyl may be optionallysubstituted with 1 or 2 substituents independently selected from(C₁-C₆)alkyl, (C₁-C₅)alkoxy, OH, CN, CF₃, halo and NR⁴³R⁴⁴;heterocycloalkyl is a C-linked or N-linked 3 to 9 membered non-aromatic,mono- or bi-cyclic ring, optionally fused to an aryl group, wherein saidheterocycloalkyl ring contains:1 or 2 NR⁴⁵ atoms, orone N— atom, orone N— atom and one NR⁴⁵, orone N— atom, one NR⁴⁵ and an S(O)_(p) or an O atom, orone N— atom and an S(O)_(p) or an O atom, orone S atom, orone O atom;optionally containing, where possible, 1 or 2 double bonds; andoptionally substituted on carbon with 1 or 2 substituents independentlyselected from (C₁-C₆)alkyl, (C₁-C₆)alkoxy, OH, CN, CF₃, halo, ═O,NR⁴⁶R⁴⁷, —C(O)NR⁴⁶R⁴⁷, bivalent substituent —OCH₂CH₂O-(wherein theterminal oxygen atoms are attached to the same ring carbon atom),bivalent substituent —CH₂NHCH₂— (wherein the terminal carbon atoms areattached to the same ring carbon atom), atetrahydro-1,1-dioxido-3-thienyl group, and aryl, wherein said(C₁-C₆)alkyl may be optionally substituted by aryl, (C₁-C₆)alkoxy or OH;and wherein each aryl group may be optionally substituted with(C₁-C₆)alkoxy (which in turn may be optionally substituted by NR³⁴R³⁵),(C₁-C₆)alkyl, OH, CF₃ and halo;aryl is an aromatic ring containing 6 or 10 carbon atoms; wherein,unless otherwise stated, said aryl may be optionally substituted with 1,2 or 3 substituents independently selected from (C₁-C₆)alkyl,(C₁-C₆)alkoxy, OH, halo, CN, CF₃ and NR⁴⁸R⁴⁹;heteroaryl is a 5, 6, 9 or 10 membered aromatic ring, containing from 1or 2 N atoms and, optionally, an NR⁵⁰ atom, or one NR⁵⁰ atom and an S oran O atom, or one S atom, or one O atom; wherein, unless otherwisestated, said heteroaryl may be optionally substituted with 1, 2 or 3substituents independently selected from (C₁-C₆)alkyl, (C₁-C₆)alkoxy,OH, halo, CN, CF₃ and NR⁵¹R⁵²;R⁴⁵ is selected from H, (C₁-C₆)alkyl, C(O)(C₁-C₆)alkyl,C(O)O(C₁-C₆)alkyl and aryl, wherein said (C₁-C₆)alkyl is optionallysubstituted with a group selected from (C₁-C₃)alkoxy, OH, halo,heterocycloalkyl and NR²⁹R³⁰; and wherein said C(O)O(C₁-C₆)alkyl isoptionally substituted with an aryl group;R⁵⁰ is selected from H, (C₁-C₆)alkyl and C(O)O(C₁-C₆)alkyl, wherein said(C₁-C₆)alkyl may be optionally substituted with a group selected from(C₁-C₃)alkoxy, OH, halo, (C₃-C₆)cycloalkyl and NR⁵³R⁵⁴;R⁴³, R⁴⁴, R⁴⁶, R⁴⁷, R⁴⁸, R⁴⁹, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷R⁵⁸ andR⁵⁹ are each independently selected from H and (C₁-C₆)alkyl;or pharmaceutically acceptable salts thereof.

For compounds of formula (IC), embodiments of the invention includethose wherein each of R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are as definedherein above in embodiments of the invention concerning compounds offormula (I).

In one embodiment, the present invention provides a compound of formula(I), (IA), (IB), (IC), (ID) or (IE) having a p38 alpha pIC₆₀ figure of5.0 or greater.

In another embodiment, the present invention provides a compound offormula (I), (IA), (IB), (IC), (ID) or (1E) having a p38 alpha pIC₅₀figure of 6.0 or greater.

In yet another embodiment, the present invention provides a compound offormula (I), (IA), (IB), (IC), (ID) or (1E) having a p38 alpha pIC₆₀figure of 7.0 or greater.

In a yet further embodiment, the present invention provides a compoundof formula (I), (IA), (IB), (IC), (ID) or (IE) having a p38 alpha pIC₆₀figure of 8.5 or greater.

In the context of the above embodiments, p38 alpha pIC₅₀ figures aredetermined according to the p38 alpha enzyme assay described hereinbelow.

DEFINITIONS

Unless otherwise stated, halo is selected from CI, F, Br and I;

Cycloalkyl is as defined above. Examples of suitable cycloalkyl groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclopentene, cyclopenta-1,3-diene, cyclohexene and cyclohexa-1,4-diene(optionally substituted as stated above). Examples of suitablecycloalkyl groups, when fused with aryl, include indanyl and1,2,3,4-tetrahydronaphthyl (optionally substituted as stated above).

Heterocycloalkyl is as defined above. Examples of suitableheterocycloalkyl groups include oxiranyl, aziridinyl, azetidinyl,tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl,N-methylpiperidinyl, morpholinyl, N-methyl morpholinyl, thiomorpholinyl,thiomorpholinyl-1-oxide, thiomorpholinyl-1,1-dioxide, piperazinyl,N-methylpiperazinyl, azepinyl oxazepinyl, diazepinyl,1,2,3,4-tetrahydropyridinyl and

(optionally substituted as stated above). Examples of suitableheterocycloalkyl groups, when fused with aryl or heteroaryl, include1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,tetrahydroimidazopyrazine, tetrahydroimidazopyridine and indolinyl(optionally substituted as stated above).

Aryl is as defined above. Examples of suitable aryl groups includephenyl and naphthyl (optionally substituted as stated above).

Heteroaryl is as defined above. Examples of suitable heteroaryl groupsinclude thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl,thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, indolyl, benzimidazolyl, benzotriazolyl, quinolinyl andisoquinolinyl (optionally substituted as stated above).

Unless otherwise stated alkyl, alkoxy, alkenyl and alkynyl groupscontaining the requisite number of carbon atoms can be branched orunbranched. Examples of suitable alkyl groups include methyl, ethyl,n-propyl, i-propyl, n-butyl, sec-butyl and t-butyl. Examples of suitablealkoxy groups include methoxy (—OCH₃), ethoxy

(—OCH₂CH₃), n-propoxy, i-propoxy, n-butoxy, sec-butoxy and t-butoxy.Examples of suitable alkenyl groups include 1,1-ethylenyl,1,2-ethylenyl, 1,1-propylenyl, 1,2-propylenyl, 1,3-propylenyl and2,2-propylene. Examples of suitable alkynyl groups include prop-1-ynyl,but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2-ynyl and hex-1-ynyl.

The term ‘C-linked’, such as in ‘C-linked heterocycloalkyl’, means thatthe heterocycloalkyl group is joined via a ring carbon atom.

The term ‘N-linked’, such as in ‘N-linked heterocycloalkyl’, means thatthe heterocycloalkyl group is joined via a ring nitrogen atom.

“Pharmaceutically acceptable salt” means a physiologically ortoxicologically tolerable salt and includes, when appropriate,pharmaceutically acceptable base addition salts and pharmaceuticallyacceptable acid addition salts. For example (i) where a compound of theinvention contains one or more acidic groups, for example carboxygroups, pharmaceutically acceptable base addition salts that can beformed include sodium, potassium, calcium, magnesium and ammonium salts,or salts with organic amines, such as, diethylamine, N-methyl-glucamine,diethanolamine or amino acids (e.g. lysine) and the like; (ii) where acompound of the invention contains a basic group, such as an aminogroup, pharmaceutically acceptable acid addition salts that can beformed include hydrochlorides, hydrobromides, sulfates, phosphates,acetates, citrates, lactates, tartrates, mesylates, tosylates,benzenesulfonates, maleates, fumarates, xinafoates,p-acetamidobenzoates, succinates, ascorbates, oleates, bisulfates andthe like.

In one embodiment, pharmaceutically acceptable salts may include saltsof pharmaceutically acceptable organic acids, especially carboxylic andsulfonic acids, including, but not limited to, acetate, adipate,alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate,butyrate, camphorate, camphorsulfonate, camsylate, citrate,p-chlorobenzenesulfonate, cyclopentate, 2,5-d ichlorobesylate,digluconate, edisylate, esylate, fumarate, formate, gluconate,glucoheptanoate, glutamate, glutarate, glycerophosphate, glycolate,heptanoate, hexanoate, hippurate, 2-hydroxyethane sulfonate, lactate,lactobionate, laurate, malate, maleate, malonate, mandelate,methanesulfonate, 2-naphthalenesulfonate, napsylate, nicotinate,orotate, oxalate, pantothenate, pamoate, pamoic, pectinate,3-phenylpropionate, pivalate, propionate, pivalate, saccharin,salicylate, stearate, succinate, tartrate, trans-cinnamate,trifluoroacetate, xinafoate, xylate (p-xylene-2-sulfonic acid),undecanoate; and of inorganic acids such as hydrobromide, hydrochloride,hydroiodide, sulphate, bisulfate, phosphate, nitrate, hemisulfate,thiocyanate, persulfate, phosphoric and sulfonic acids.

Salts which are not pharmaceutically acceptable may still be valuable asintermediates.

Hemisalts of acids and bases can also be formed, for example,hemisulfate and hemicalcium salts.

For a review of suitable salts, see “Handbook of Pharmaceutical Salts:Properties, Selection and Use” by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002).

“Prodrug” refers to a compound which is convertible in vivo by metabolicmeans (e.g. by hydrolysis, reduction or oxidation) to a compound of theinvention. Suitable groups for forming pro-drugs are described in ‘ThePractice of Medicinal Chemistry, 2^(nd) Ed. pp 561-585 (2003) and in F.J. Leinweber, Drug Metab. Res., 18, 379. (1987).

The compounds of the invention can exist in both unsolvated and solvatedforms. The term ‘solvate’ is used herein to describe a molecular complexcomprising the compound of the invention and a stoichiometric amount ofone or more pharmaceutically acceptable solvent molecules, for example,ethanol. The term ‘hydrate’ is employed when the solvent is water.

Where compounds of the invention exist in one or more geometrical,optical, enantiomeric, diastereomeric and tautomeric forms, includingbut not limited to cis- and trans-forms, E- and Z-forms, R-, S- andmeso-forms, keto-, and enol-forms. Unless otherwise stated a referenceto a particular compound includes all such isomeric forms, includingracemic and other mixtures thereof. Where appropriate such isomers canbe separated from their mixtures by the application or adaptation ofknown methods (e.g. chromatographic techniques and recrystallisationtechniques). Where appropriate such isomers can be prepared by theapplication of adaptation of known methods (e.g. asymmetric synthesis).

The skilled person will recognise that the compounds of the inventionmay be prepared, in known manner, in a variety of ways. The routes beloware merely illustrative of some of the methods that can be employed forthe synthesis of compounds of formula (I).

Accordingly, the present invention provides a process for preparing acompound of formula (I) or a pharmaceutically-acceptable salt thereofwhich comprises functionalisation of compound of formula (II) whereinR¹, R², R³, R⁵, R⁶ and R⁷ are as defined in claim 1 and L₁ is a leavinggroup, typically halogen, and optionally carrying out one or more of thefollowing:

-   -   (i) converting the compound to another compound of formula (I);    -   (ii) forming a pharmaceutically-acceptable salts of the        compound.

The functionalisation of the C⁵ position of 2(1H)-pyrazinone ring ofcompound of formula (II) may involve formation of a C—H, C—C, C—N, C—Sor C—O bond. The reaction may be catalysed by a transition metal such aspalladium, or copper and conveniently performed in an organic solventsuch toluene, N-methylpyrrolidin-2-one, tetrahydrofuran, 1,4-dioxane,methanol, ethanol, ethyl acetate, N,N-dimethylformamide,N,N-dimethylacetamide, 1,2-dimethoxyethane and optionally in thepresence of an appropriate base such as triethylamine,N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, cesiumcarbonate, potassium phosphate, sodium tert-butoxide and at atemperature in the range, for example, of from 0 to 200° C. In thedehalogenation reactions, reducing agents such as hydrogen gas, sodiumformate, ammonium formate, formic acid, 1,3- or 1,4-cyclohexadiene maybe used. Typically, where R⁴ is H, ammonium formate in ethanol in thepresence of N,N-diisopropylethylamine can be used.

Alternatively, a compound of formula (I) or apharmaceutically-acceptable salt thereof may be prepared by reacting acompound of formula (III) wherein W¹ represents a leaving group (forexample hydroxyl, alkoxy, acyloxy or halogen) with a compound of formula(IV).

Typically, if compound (III) is in an ester form such as methyl or ethylester, the reaction may be carried out by treating a compound of formula(III) with a compound of formula (IV) in the presence of anorganomagnesium halide, typically iso-propylmagnesium chloride orcyclopentylmagnesium bromide, or trialkylaluminium in a suitableanhydrous solvent such as diethyl ether, tetrahydrofuran, 1,4-dioxane,toluene, 1,2-dimethoxyethane, and at a temperature in the range, forexample, of from −78° C. to ambient temperature (25° C.). Alternatively,reaction of (III) and (IV) may be performed under thermal conditions inin a suitable organic solvent or diluent, for example toluene,tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-oneat elevated temperature, for example in the range of from 40 to 130° C.

In the case where W¹ is OH, the carboxylic acid can be first convertedto an acid halide by treatment with oxalyl halide at a temperaturebetween 5° C. and 35° C. in an inert solvent such as dichloromethane.Typically, the acid halide is then treated with the amine of formula(IV) in an inert solvent such as dichloromethane in the presence of anon-nucleophilic base such as N, N-diisopropylethylamine ortriethylamine; or, when W¹ is OH, the carboxylic acid can be firstconverted to other suitable reactive derivative of formula (III), forexample, a mixed anhydride, for example an anhydride formed by thereaction of the acid and a chloroformate such as isobutyl chloroformate;an ester, formed by reaction with an alcohol in the presence of acid orbase; an active ester, for example an ester formed by the reaction ofthe acid with a phenol such as pentafluorophenol, with an ester such aspentafluorophenyl trifluoroacetate or with an alcohol such as

N-hydroxybenzotriazole;

or, the acid of formula (III, W¹=OH) can be reacted with an amine offormula (IV) in the presence of an amide coupling agent such asdicyclohexylcarbodiimide, Pybop(benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide,HATU(2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphatemethanaminium) or PyBroP (bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate).

If the compound (III) is an acid form, such compounds may be prepared byhydrolysis of corresponding ester under basic (for example treating withlithium hydroxide in methanol-water mixture), hydrogenolytic (forexample treating with hydrogen in appropriate solvent in the presence ofpalladium on charcoal) or acidic conditions (for example treating with48% HBr or trifluoroacetic acid).

Compounds of formula (II) can be prepared from the compound of formula(V) wherein W¹ represents a leaving group (for example hydroxyl, alkoxy,acyloxy or halogen), R¹, R², R³ and R⁵ as defined in the formula (I) andL¹ is a leaving group, typically halogen, using methods described forpreparation of compound of formula (I) from a compound of formula (III).

Additionally, compounds of formula (III) can be conveniently preparedfrom the compound of formula (V) wherein W¹ represents the alkoxy groupand R¹, R², R³, R⁵ and L¹ are as defined above, using methods describedfor preparation of a compound of formula (I) from compound of formula(II).

Compounds of formula (V) can be conveniently prepared from the compoundof formula (VI), wherein L¹ and L² are leaving groups, typicallyhalogen, and R¹, R², R³ are as defined above and W¹ in an alkoxy group,by selective nucleophilic aromatic substitution of the L² leaving groupwith a variety nucleophiles of formula (VII) wherein Y representshydrogen (for example in amines, anilines, alcohols, phenols,thioalcohols, thiophenols) or a metal (for example in cyanides, Grignardreagents). The reaction can be performed in a suitable organic solventsuch toluene, N-methylpyrrolidin-2-one, tetrahydrofuran, 1,4-dioxane,methanol, ethanol, ethyl acetate, N,N-dimethylformamide,N,N-dimethylacetamide, 1,2-dimethoxyethane and optionally in thepresence of an appropriate base such as triethylamine,N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),sodium carbonate, potassium carbonate, cesium carbonate, sodiumtert-butoxide, sodium hydride and at a temperature in the range, forexample, of from −78 to 200° C., most conveniently at ambienttemperature (25° C.). In the case where R⁵ is (CR¹⁴R¹⁵)_(m)NR¹⁶R¹⁷wherein R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are as defined in claim 1 and m=0, thereaction is typically carried out in tetrahydrofuran at ambient orelevated temperature in the presence of tertiary amine such asN,N-diisopropylethylamine.

Also, compounds of formula (V) where R⁵ aryl, heteroaryl, alkenyl,alkynyl or CH₂R¹⁶, wherein, R¹⁶ is as defined in claim 1, can beprepared in transition metal catalysed cross-coupling reactions (forexample Suzuki, Negishi, Kumada, Stille, Sonogashira, Hiyama or Heckcross-coupling reactions) from the compound of formula (VI) and formula(VII) such as alkenes, alkynes, boronic acids and esters thereof,stannanes and silanes. The reaction can be performed in an organicsolvent such toluene, N-methylpyrrolidin-2-one, tetrahydrofuran,1,4-dioxane, methanol, ethanol, ethyl acetate, N,N-dimethylformamide,N,N-dimethylacetamide, 1,2-dimethoxyethane in the presence of anappropriate base such as triethylamine, N,N-diisopropylethylamine,sodium carbonate, potassium carbonate, cesium carbonate, potassiumphosphate, sodium tert-butoxide, sodium hydride and at a temperature inthe range, for example, of from 0 to 150° C.

In another method, compounds of formula (VI) can be prepared from thecompound of formula (IX) wherein R¹, R², R³ are as defined above and W¹in an alkoxy group, by treatment with suitable halogenating reagents,such as N-halosuccinimide in the presence of a base like sodiumcarbonate and a suitable solvent such as, for exampleN,N-dimethylformamide.

Compounds of formula (VI) can be conveniently prepared by treatment ofthe compound of formula (VIII) or a salt thereof, wherein R¹, R², R³ areas defined above and W¹ is an alkoxy group, with the correspondingoxalyl halides such as oxalyl bromide or oxalyl chloride in a suitablesolvent such as for example N,N-dimethylformamide, chlorobenzene,dichlorobenzene, chloroform optionally in the presence of suitable saltsuch as for example tetraethylammonium bromide and at a temperature inthe range, for example, of from 20 to 200° C. Typically, the reaction iscarried out with oxalyl bromide in 1,2-dichlorobenzene at 100° C.

Compounds of formula (VIII), where R¹, R² and R³ areas defined above andW¹ is an alkoxy group can be conveniently prepared by treatment of thecompound of formula (X) or a salt thereof, with a compound of formula(XI) wherein L³ is a leaving group, typically halogen, and is as definedabove. The reaction can be performed in the presence of anon-nucleophilic base, such as N,N-diisopropylethylamine, triethylamine,sodium carbonate, in an inert solvent, such as toluene,N-methylpyrrolidin-2-one, tetrahydrofuran, 1,2-dimethoxyethane,1,4-dioxane, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamideand at a temperature in the range, for example, of from 0 to 150° C.,preferably in tetrahydrofuran in the presence N,N-diisopropylethylamineat reflux.

Alternatively, compounds of formula (VIII) can be prepared in reactionof a compound of formula (X) with a compound of formula (XII), whereinR³ is as defined above, and cyanides such as, for example sodiumcyanide, potassium cyanide or trimethylsilyl cyanide in a suitablesolvent such for example acetonitrile, acetic acid, methanol, ethanol,water, acetone, toluene optionally in the presence of suitable Lewisacid such as for example trifluoromethanesulphonic acid, magnesiumsulphate, nickel chloride, zinc chloride and at a temperature in therange, for example, of from 0 to 200° C. most conveniently at ambienttemperature (25° C.).

Compounds of formula (III) can also be conveniently prepared bytreatment of a compound of formula (XIII), wherein R¹, R², R⁵ are asdefined above and W¹ is an alkoxy group, with a compound of formula(XIV), wherein R³ and R⁴ are as defined above, in the presence of basein a suitable organic solvent such as for example methanol.

Compounds of formula (IX), wherein R¹, R² and R³ areas defined above andW¹ is an alkoxy or alkylamino group can similarly be prepared bytreatment of a compound of formula (XIII) with a compound of formula(XIV), where R³ in H.

Compounds of formula (XIII) can be conveniently prepared from a compoundof formula (X) and a corresponding amino acid derivative (XV), whereinR⁵ is defined hereinabove and W² is the hydroxyl or alkoxy group, in thestandard amide coupling reactions using the methods described forpreparation of compound of formula (I) from a compound of formula (III).Homochiral compounds of formula (VII), wherein R⁵ is(CR¹⁴R¹⁵)_(m)NR¹⁶R¹⁷ where m=0, R¹⁷═H and R¹⁶ is as defined in claim 1,can by conveniently prepared from a compound of formula (XVI) wherein Z,X, R²² and R²³ are as defined in claim 1 by treatment with a suitableacid, such as for example hydrochloric or trifluoroacetic acid, in asuitable organic solvent, such as for example methanol, ethanol or1,4-dioxane and at a temperature in the range, for example, of from 0 to100° C., most conveniently at ambient temperature (25° C.). Typically,the reaction is carried out with hydrogen chloride in1,4-dioxane/methanol at ambient temperature (25° C.).

Compounds of formula (XVI) wherein Z, X, R²² and R²³ are as defined inclaim 1, can by conveniently prepared by reacting a compound of formula(XVII) with a suitable derivative of a compound of formula (XVIII),wherein Z and X are as defined in claim 1 and M is a metal (for examplemagnesium, aluminium, cerium, lithium, indium) or metaloid (for exampleboron) in a suitable solvent, such as for example toluene,tetrahydrofuran, 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane ordichloromethane and optionally in the presence of appropriate metalcatalyst, such as for examplebis(acetonitrile)[(1,2,5,6-η)-1,5-cyclooctadiene]-rhodium,tetrafluoroborate and at a temperature in the range, for example, offrom −78 to 100° C. Typically, the reaction is carried out with Grignardreagents in dichloromethane at a temperature in the range, for example,of from −40 to 0° C.

Compound of formula (XVII) wherein R²² and R²³ are as defined in claim 1can by conveniently prepared by reacting a compound of formula (XIX)with a suitable sulfinimine in a suitable solvent, such as for exampletoluene, tetrahydrofuran, 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, dichloromethane in the presence of suitabledehydrating agent, such as for example titanium(IV) ethoxide, copper(II)sulphate, sodium(I) sulphate and at a temperature in the range, forexample, of from 0 to 100° C., most conveniently at ambient temperature(25° C.). Typically, the reaction is carried out with (R) or (S)2-methyl-2-propanesulfinamide in the presence of titanium(IV) ethoxidein tetrahydrofuran at ambient temperature (25° C.).

Compounds of formula (IV), (VII), (X), (XI), (XII), (XIV), (XV), (XIX)are commercially available, are known in the literature, or may beprepared using known techniques by those skilled in the art.

Compounds of formula (X), where R¹, R² and R³ areas defined above (inparticular R¹═F and R²=Me) and W¹ is an alkoxy group can be convenientlyprepared by reduction of compound of formula (XX) where Z=hydrogen,chloro, bromo or iodo, and Y=nitro, nitroso or amino. Typical reducingagents include, for example, hydrogen gas, sodium formate, ammoniumformate, formic acid, 1,3- or 1,4-cyclohexadiene. Typically the reactionmay be catalysed by by a transition metal such as palladium andconveniently performed in an organic solvent such as, but not limitedby, toluene, N-methylpyrrolidin-2-one, tetrahydrofuran, 1,4-dioxane,methanol, ethanol, ethyl acetate, N,N-dimethylformamide,N,N-dimethylacetamide, 1,2-dimethoxyethane and optionally in thepresence of an appropriate base such as triethylamine,N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, cesiumcarbonate, potassium phosphate, sodium hydroxide and at a temperature inthe range, for example, of from 0 to 200° C.

Preferably when R¹═F and R²=Me and W¹=OMe, X═Cl and Y=nitro the reactionis carried out using Pd/C and either hydrogengas/N,N-diisopropylethylamine or ammonium formate in ethanol attemperatures between room temperature and 80° C.

Compounds of formula (XX) where W¹ is alkoxy can conveniently beprepared from (XX) where W¹ is OH by an esterification reaction. Thiscan be carried out using the an alcohol solvent such as methanol orethanol under for example acid catalysis. Such acids can includesulfuric acid or hydrochloric acid or via addition of excesschlorotrimethylsilane and can be at a temperature in the range, forexample, of from 0 to 150° C., preferably in methanol at roomtemperature with excess chlorotrimethylsilane.

Compounds of the type (XX) W¹ is OH, Z═Cl, R¹═F R²=Me are are known inthe literature (such as DE 3441788), or may be prepared using knowntechniques by those skilled in the art.

This route offers significant advantages over alternative literatureroutes which proceed via potentially explosive nitroaryl diazonium salts(J Chem Soc 1960, 672-6).

In one embodiment, the present invention provides a process forpreparing a compound of formula (I) as defined herein above, or apharmaceutically-acceptable salt thereof, by the reaction of a compoundof formula (III):

wherein R¹, R², R³, R⁴ and R⁵ are as defined in formula (I) and W¹ is aleaving group; with a compound of formula (IV):

wherein R⁶ and R⁷ are as defined in formula (I).

It will be appreciated by those skilled in the art that in the processesof the present invention certain functional groups such as hydroxy,carboxy or amino groups in the starting reagents or intermediatecompounds may need to be protected by protecting groups. Thus, thepreparation of the compounds of formula (I) may involve at a certainstage protection with and/or the removal of one or more protectinggroups. The protection and deprotection of functional groups isdescribed in ‘Protective Groups in Organic Synthesis’, 2nd edition, T.W.Greene and P.G.M. Wuts, Wiley-Interscience (1991) and ‘ProtectingGroups’, P. J. Kocienski, Georg Thieme Verlag (1994). The compounds offormula (I) above may be converted to a pharmaceutically acceptable saltusing conventional methods.

Some of the intermediate compounds used in the preparation of compoundsof formula (I) are themselves novel compounds. Accordingly, in oneembodiment the present invention further provides a compound of formula(VA) or a salt thereof

wherein:W¹ is OH or (C₁-C₄)alkoxy;R¹ and R² are independently selected from H, (C₁-C₄)alkyl and F;

R⁴ is H or Br;

R²² and R²³ each independently represent methyl, or R²² and R²³ togetherwith the carbon atom to which they are both attached form a cyclopropylring; andR²⁶ is selected from OH, OCH₂Ph or OCH₂CH₂Cl.

In one embodiment, the present invention provides a compound of formula(VA), or a salt thereof, wherein W¹ is OH or OMe; R¹ is H or F; R² ismethyl; R⁴ is H or Br;

R²² and R²³ each independently represent methyl, or R²² and R²³ togetherwith the carbon atom to which they are both attached form a cyclopropylring; and

R²⁶ is OH, OCH₂Ph or OCH₂CH₂Cl.

In another embodiment the present invention further provides a compoundof formula (VIA) or a salt thereof

wherein:W¹ is OH or (C₁-C₄)alkoxy; andR¹ and R² are independently selected from H, (C₁-C₄)alkyl and F.

In one embodiment, the present invention provides a compound of formula(VIA), or a salt thereof, wherein W¹ is OH or OMe; R¹ is H or F; and R²is methyl.

In another embodiment the present invention provides the compound (XXI),or a salt thereof,

The compounds of the invention have activity as pharmaceuticals, inparticular as p38 kinase inhibitors. Diseases and conditions which maybe treated with the compounds include:

1. respiratory tract: obstructive diseases of the airways including:asthma, including bronchial, allergic, intrinsic, extrinsic,exercise-induced, drug-induced (including aspirin and NSAID-induced) anddust-induced asthma, both intermittent and persistent and of allseverities, and other causes of airway hyper-responsiveness; chronicobstructive pulmonary disease (COPD); bronchitis, including infectiousand eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis;sarcoidosis; farmer's lung and related diseases; hypersensitivitypneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis,idiopathic interstitial pneumonias, fibrosis complicatinganti-neoplastic therapy and chronic infection, including tuberculosisand aspergillosis and other fungal infections; complications of lungtransplantation; vasculitic and thrombotic disorders of the lungvasculature, and pulmonary hypertension; antitussive activity includingtreatment of chronic cough associated with inflammatory and secretoryconditions of the airways, and iatrogenic cough; acute and chronicrhinitis including rhinitis medicamentosa, and vasomotor rhinitis;perennial and seasonal allergic rhinitis including rhinitis nervosa (hayfever); nasal polyposis; acute viral infection including the commoncold, and infection due to respiratory syncytial virus, influenza,coronavirus (including SARS) and adenovirus;2. bone and joints: arthritides associated with or includingosteoarthritis/osteoarthrosis, both primary and secondary to, forexample, congenital hip dysplasia; cervical and lumbar spondylitis, andlow back and neck pain; rheumatoid arthritis and Still's disease;seronegative spondyloarthropathies including ankylosing spondylitis,psoriatic arthritis, reactive arthritis and undifferentiatedspondarthropathy; septic arthritis and other infection-relatedarthopathies and bone disorders such as tuberculosis, including Potts'disease and Poncet's syndrome; acute and chronic crystal-inducedsynovitis including urate gout, calcium pyrophosphate depositiondisease, and calcium apatite related tendon, bursal and synovialinflammation; Behcet's disease; primary and secondary Sjogren'ssyndrome; systemic sclerosis and limited scleroderma; systemic lupuserythematosus, mixed connective tissue disease, and undifferentiatedconnective tissue disease; inflammatory myopathies includingdermatomyositits and polymyositis; polymalgia rheumatica; juvenilearthritis including idiopathic inflammatory arthritides of whateverjoint distribution and associated syndromes, and rheumatic fever and itssystemic complications; vasculitides including giant cell arteritis,Takayasu's arteritis, Churg-Strauss syndrome, polyarteritis nodosa,microscopic polyarteritis, and vasculitides associated with viralinfection, hypersensitivity reactions, cryoglobulins, and paraproteins;low back pain; Familial Mediterranean fever, Muckle-Wells syndrome, andFamilial Hibernian Fever, Kikuchi disease; drug-induced arthalgias,tendonititides, and myopathies;3. pain and connective tissue remodelling of musculoskeletal disordersdue to injury [for example sports injury] or disease: arthritides (forexample rheumatoid arthritis, osteoarthritis, gout or crystalarthropathy), other joint disease (such as intervertebral discdegeneration or temporomandibular joint degeneration), bone remodellingdisease (such as osteoporosis, Paget's disease or osteonecrosis),polychondritits, scleroderma, mixed connective tissue disorder,spondyloarthropathies or periodontal disease (such as periodontitis);4. skin: psoriasis, atopic dermatitis, contact dermatitis or othereczematous dermatoses, and delayed-type hypersensitivity reactions;phyto- and photodermatitis; seborrhoeic dermatitis, dermatitisherpetiformis, lichen planus, lichen sclerosus et atrophica, pyodermagangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus,pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides,toxic erythemas, cutaneous eosinophilias, alopecia areata, male-patternbaldness, Sweet's syndrome, Weber-Christian syndrome, erythemamultiforme; cellulitis, both infective and non-infective; panniculitis;cutaneous lymphomas, non-melanoma skin cancer and other dysplasticlesions; drug-induced disorders including fixed drug eruptions;5. eyes: blepharitis; conjunctivitis, including perennial and vernalallergic conjunctivitis; iritis; anterior and posterior uveitis;choroiditis; autoimmune; degenerative or inflammatory disordersaffecting the retina; ophthalmitis including sympathetic ophthalmitis;sarcoidosis; infections including viral, fungal, and bacterial;6. gastrointestinal tract: glossitis, gingivitis, periodontitis;oesophagitis, including reflux; eosinophilic gastro-enteritis,mastocytosis, Crohn's disease, colitis including ulcerative colitis,proctitis, pruritis ani; coeliac disease, irritable bowel syndrome, andfood-related allergies which may have effects remote from the gut (forexample migraine, rhinitis or eczema);7. abdominal: hepatitis, including autoimmune, alcoholic and viral;fibrosis and cirrhosis of the liver; cholecystitis; pancreatitis, bothacute and chronic;8. genitourinary: nephritis including interstitial andglomerulonephritis; nephrotic syndrome; cystitis including acute andchronic (interstitial) cystitis and Hunner's ulcer; acute and chronicurethritis, prostatitis, epididymitis, oophoritis and salpingitis;vulvo-vaginitis; Peyronie's disease; erectile dysfunction (both male andfemale);9. allograft rejection: acute and chronic following, for example,transplantation of kidney, heart, liver, lung, bone marrow, skin orcornea or following blood transfusion; or chronic graft versus hostdisease;10. CNS: Alzheimer's disease and other dementing disorders including CJDand nvCJD; amyloidosis; multiple sclerosis and other demyelinatingsyndromes; cerebral atherosclerosis and vasculitis; temporal arteritis;myasthenia gravis; acute and chronic pain (acute, intermittent orpersistent, whether of central or peripheral origin) including visceralpain, headache, migraine, trigeminal neuralgia, atypical facial pain,joint and bone pain, pain arising from cancer and tumor invasion,neuropathic pain syndromes including diabetic, post-herpetic, andHIV-associated neuropathies; neurosarcoidosis; central and peripheralnervous system complications of malignant, infectious or autoimmuneprocesses;11. other auto-immune and allergic disorders including Hashimoto'sthyroiditis, Graves' disease, Addison's disease, diabetes mellitus,idiopathic thrombocytopaenic purpura, eosinophilic fasciitis, hyper-IgEsyndrome, antiphospholipid syndrome;12. other disorders with an inflammatory or immunological component;including acquired immune deficiency syndrome (AIDS), leprosy, Sezarysyndrome, and paraneoplastic syndromes;13. cardiovascular: atherosclerosis, affecting the coronary andperipheral circulation; pericarditis; myocarditis, inflammatory andauto-immune cardiomyopathies including myocardial sarcoid; ischaemicreperfusion injuries; endocarditis, valvulitis, and aortitis includinginfective (for example syphilitic); vasculitides; disorders of theproximal and peripheral veins including phlebitis and thrombosis,including deep vein thrombosis and complications of varicose veins;14. oncology: treatment of common cancers including prostate, breast,lung, ovarian, pancreatic, bowel and colon, stomach, skin and braintumors and malignancies affecting the bone marrow (including theleukaemias) and lymphoproliferative systems, such as Hodgkin's andnon-Hodgkin's lymphoma; including the prevention and treatment ofmetastatic disease and tumour recurrences, and paraneoplastic syndromes;and,15. gastrointestinal tract: Coeliac disease, proctitis, eosinopilicgastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis,microscopic colitis, indeterminant colitis, irritable bowel disorder,irritable bowel syndrome, non-inflammatory diarrhea, food-relatedallergies which have effects remote from the gut, e.g., migraine,rhinitis and eczema.

Accordingly, the present invention further provides a compound offormula (I), (IA), (IB), (IC), (ID) or (IE) as as hereinbefore defined,or a pharmaceutically acceptable salt thereof, for use in therapy.

In another aspect, the invention provides the use of a compound offormula (I), (IA), (IB), (IC), (ID) or (IE) as as hereinbefore defined,or a pharmaceutically acceptable salt thereof, in the manufacture of amedicament for use in therapy.

In the context of the present specification, the term “therapy” alsoincludes “prophylaxis” unless there are specific indications to thecontrary. The terms “therapeutic” and “therapeutically” should beconstrued accordingly.

A further aspect of the invention provides a method of treating adisease state in a mammal suffering from, or at risk of, said disease,which comprises administering to a mammal in need of such treatment atherapeutically effective amount of a compound of formula (I), (IA),(IB), (IC), (ID) or (IE) as as hereinbefore defined, or apharmaceutically acceptable salt thereof.

The present invention also provides the use of a compound of formula(I), (IA), (IB), (IC), (ID) or (IE) as hereinbefore defined, or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for use in the treatment of chronic obstructive pulmonarydisease (COPD) (such as irreversible COPD).

The present invention also provides a compound of formula (I), (IA),(IB), (IC), (ID) or (IE) as hereinbefore defined, or a pharmaceuticallyacceptable salt thereof, for treating COPD.

The present invention also provides the use of a compound of formula(I), (IA), (IB), (IC), (ID) or (IE) as hereinbefore defined, or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for use in the treatment of asthma.

The present invention also provides a compound of formula (I), (IA),(IB), (IC), (ID) or (IE) as hereinbefore defined, or a pharmaceuticallyacceptable salt thereof, for treating asthma.

The present invention further provides a method of treating chronicobstructive pulmonary disease (COPD) (such as irreversible COPD), in awarm-blooded animal, such as man, which comprises administering to amammal in need of such treatment an effective amount of a compound offormula (I), (IA), (IB), (IC), (ID) or (IE) as hereinbefore defined, ora pharmaceutically acceptable salt thereof.

The present invention further provides a method of treating asthma in awarm-blooded animal, such as man, which comprises administering to amammal in need of such treatment an effective amount of a compound offormula (I), (IA), (IB), (IC), (ID) or (IE) as hereinbefore defined, ora pharmaceutically acceptable salt thereof.

In order to use a compound of the invention for the therapeutictreatment of a warm-blooded animal, such as man, said ingredient isnormally formulated in accordance with standard pharmaceutical practiceas a pharmaceutical composition.

Therefore in another aspect the present invention provides apharmaceutical composition that comprises a compound of the invention ashereinbefore defined and a pharmaceutically acceptable adjuvant, diluentor carrier. In a further aspect the present invention provides a processfor the preparation of said composition, which comprises mixing activeingredient with a pharmaceutically acceptable adjuvant, diluent orcarrier. Depending on the mode of administration, the pharmaceuticalcomposition will, for example, comprise from 0.05 to 99% w (percent byweight), such as from 0.05 to 80% w, for example from 0.10 to 70% w,such as from 0.10 to 50% w, of active ingredient, all percentages byweight being based on total composition.

The pharmaceutical compositions of this invention may be administered instandard manner for the disease condition that it is desired to treat,for example by topical (such as to the lung and/or airways or to theskin), oral, rectal or parenteral administration. For these purposes thecompounds of this invention may be formulated by means known in the artinto the form of, for example, aerosols, dry powder formulations,tablets, capsules, syrups, powders, granules, aqueous or oily solutionsor suspensions, (lipid) emulsions, dispersible powders, suppositories,ointments, creams, drops and sterile injectable aqueous or oilysolutions or suspensions.

A suitable pharmaceutical composition of this invention is one suitablefor oral administration in unit dosage form, for example a tablet orcapsule, which contains between 0.1 mg and 1 g of active ingredient.

In another aspect a pharmaceutical composition of the invention is onesuitable for intravenous, subcutaneous or intramuscular injection. Eachpatient may receive, for example, an intravenous, subcutaneous orintramuscular dose of 0.01 mgkg⁻¹ to 100 mgkg⁻¹ of the compound, forexample in the range of 0.1 mgkg⁻¹ to 20 mgkg⁻¹ of this invention, thecomposition being administered 1 to 4 times per day. The intravenous,subcutaneous and intramuscular dose may be given by means of a bolusinjection. Alternatively the intravenous dose may be given by continuousinfusion over a period of time. Alternatively each patient will receivea daily oral dose, which is approximately equivalent to the dailyparenteral dose, the composition being administered 1 to 4 times per day

Another suitable pharmaceutical composition of this invention is onesuitable for inhaled administration, inhalation being a particularlyuseful method for administering the compounds of the invention whentreating respiratory diseases such as chronic obstructive pulmonarydisease (COPD) or asthma. When administered by inhalation the compoundsof formula (I) may be used effectively at doses in the μg range, forexample 0.1 to 500 μg, 0.1 to 50 μg, 0.1 to 40 μg, 0.1 to 30 μg, 0.1 to20 μg, 0.1 to 10 μg, 5 to 10 μg, 5 to 50 μg, 5 to 40 μg, 5 to 30 μg, 5to 20 μg, 5 to 10 μg, 10 to 50 μg, 10 to 40 μg 10 to 30 μg, or 10 to 20μg of active ingredient.

In an embodiment of the invention, there is provided a pharmaceuticalcomposition comprising a compound of the invention as hereinbeforedefined, in association with a pharmaceutically acceptable adjuvant,diluent or carrier, which is formulated for inhaled administration.

When administered by inhalation, metered dose inhaler devices may beused to administer the active ingredient, dispersed in a suitablepropellant and with or without additional excipients such as ethanol,surfactants, lubricants or stabilising agents. Suitable propellantsinclude hydrocarbon, chlorofluorocarbon and hydrofluoroalkane (e.g.heptafluoroalkane) propellants, or mixtures of any such propellants.Preferred propellants are P134a and P227, each of which may be usedalone or in combination with other propellants and/or surfactant and/orother excipients. Nebulised aqueous suspensions or, preferably,solutions may also be employed, with or without a suitable pH and/ortonicity adjustment, either as a unit-dose or multi-dose formulations.

Dry powder inhalers may be used to administer the active ingredient,alone or in combination with a pharmaceutically acceptable carrier, inthe later case either as a finely divided powder or as an orderedmixture. The dry powder inhaler may be single dose or multi-dose and mayutilise a dry powder or a powder-containing capsule.

Metered dose inhaler, nebuliser and dry powder inhaler devices are wellknown and a variety of such devices are available.

The invention further relates to combination therapies wherein acompound of the invention or a pharmaceutical composition or formulationcomprising a compound of the invention, is administered concurrently orsequentially or as a combined preparation with another therapeutic agentor agents, for the treatment of one or more of the conditions listed.

In particular, for the treatment of the inflammatory diseases such as(but not restricted to) rheumatoid arthritis, osteoarthritis, asthma,allergic rhinitis, chronic obstructive pulmonary disease (COPD),psoriasis, and inflammatory bowel disease, the compounds of theinvention may be combined with agents listed below.

Non-steroidal anti-inflammatory agents (hereinafter NSAIDs) includingnon-selective cyclo-oxygenase COX-1/COX-2 inhibitors whether appliedtopically or systemically (such as piroxicam, diclofenac, propionicacids such as naproxen, flurbiprofen, fenoprofen, ketoprofen andibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac,azapropazone, pyrazolones such as phenylbutazone, salicylates such asaspirin); selective COX-2 inhibitors (such as meloxicam, celecoxib,rofecoxib, valdecoxib, lumarocoxib, parecoxib and etoricoxib);cyclo-oxygenase inhibiting nitric oxide donors (CINODs);glucocorticosteroids (whether administered by topical, oral,intramuscular, intravenous, or intra-articular routes); methotrexate;leflunomide; hydroxychloroquine; d-penicillamine; auranofin or otherparenteral or oral gold preparations; analgesics; diacerein;intra-articular therapies such as hyaluronic acid derivatives; andnutritional supplements such as glucosamine.

The present invention still further relates to the combination of acompound of the invention together with a cytokine or agonist orantagonist of cytokine function, (including agents which act on cytokinesignalling pathways such as modulators of the SOCS system) includingalpha-, beta-, and gamma-interferons; insulin-like growth factor type I(IGF-1); interleukins (IL) including IL1 to 17, and interleukinantagonists or inhibitors such as anakinra; tumour necrosis factor alpha(TNF-α) inhibitors such as anti-TNF monoclonal antibodies (for exampleinfliximab; adalimumab, and CDP-870) and TNF receptor antagonistsincluding immunoglobulin molecules (such as etanercept) andlow-molecular-weight agents such as pentoxyfylline.

In addition the invention relates to a combination of a compound of theinvention with a monoclonal antibody targeting B-Lymphocytes (such asCD20 (rituximab), MRA-aILI6R and T-Lymphocytes, CTLA4-Ig, HuMax II-15).

The present invention still further relates to the combination of acompound of the invention with a modulator of chemokine receptorfunction such as an antagonist of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4,CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C—C family);CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C—X−C family) and CX₃CR1for the C—X₃—C family.

The present invention further relates to the combination of a compoundof the invention with an inhibitor of matrix metalloprotease (MMPs),i.e., the stromelysins, the collagenases, and the gelatinases, as wellas aggrecanase; especially collagenase-1 (MMP-1), collagenase-2 (MMP-8),collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10),and stromelysin-3 (MMP-11) and MMP-9 and MMP-12, including agents suchas doxycycline.

The present invention still further relates to the combination of acompound of the invention and a leukotriene biosynthesis inhibitor,5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein(FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin;Abbott-79175; Abbott-85761; aN-(5-substituted)-thiophene-2-alkylsulfonamide;2,6-di-tert-butylphenolhydrazones; a methoxytetrahydropyrans such asZeneca ZD-2138; the compound SB-210661; a pyridinyl-substituted2-cyanonaphthalene compound such as L-739,010; a 2-cyanoquinolinecompound such as L-746,530; or an indole or quinoline compound such asMK-591, MK-886, and BAY x 1005.

The present invention further relates to the combination of a compoundof the invention and a receptor antagonist for leukotrienes (LT) B4,LTC4, LTD4, and LTE4 selected from the group consisting of thephenothiazin-3-1s such as L-651,392; amidino compounds such asCGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamidessuch as BIIL 284/260; and compounds such as zafirlukast, ablukast,montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913,iralukast (CGP 45715A), and BAY x 7195.

The present invention still further relates to the combination of acompound of the invention and a phosphodiesterase (PDE) inhibitor suchas a methylxanthanine including theophylline and aminophylline; aselective PDE isoenzyme inhibitor including a PDE4 inhibitor aninhibitor of the isoform PDE4D, or an inhibitor of PDE5.

The present invention further relates to the combination of a compoundof the invention and a histamine type 1 receptor antagonist such ascetirizine, loratadine, desloratadine, fexofenadine, acrivastine,terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine,promethazine, cyclizine, or mizolastine; applied orally, topically orparenterally.

The present invention still further relates to the combination of acompound of the invention and a proton pump inhibitor (such asomeprazole) or a gastroprotective histamine type 2 receptor antagonist.

The present invention further relates to the combination of a compoundof the invention and an antagonist of the histamine type 4 receptor.

The present invention still further relates to the combination of acompound of the invention and an alpha-1/alpha-2 adrenoceptor agonistvasoconstrictor sympathomimetic agent, such as propylhexedrine,phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine,naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozolinehydrochloride, xylometazoline hydrochloride, tramazoline hydrochlorideor ethylnorepinephrine hydrochloride.

The present invention further relates to the combination of a compoundof the invention, or a pharmaceutically acceptable salt thereof, and ananticholinergic agent including a muscarinic receptor (M1, M2, and M3)antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropiumbromide, tiotropium bromide, oxitropium bromide, pirenzepine ortelenzepine.

The present invention still further relates to the combination of acompound of the invention and a beta-adrenoceptor agonist (includingbeta receptor subtypes 1-4) such as isoprenaline, salbutamol,formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate,pirbuterol, or indacaterol or a chiral enantiomer thereof.

The present invention further relates to the combination of a compoundof the invention and a chromone, such as sodium cromoglycate ornedocromil sodium.

The present invention still further relates to the combination of acompound of the invention with a glucocorticoid, such as flunisolide,triamcinolone acetonide, beclomethasone dipropionate, budesonide,fluticasone propionate, ciclesonide or mometasone furoate.

The present invention further relates to the combination of a compoundof the invention with an agent that modulates a nuclear hormone receptorsuch as PPARs.

The present invention still further relates to the combination of acompound of the invention together with an immunoglobulin (Ig) or Igpreparation or an antagonist or antibody modulating Ig function such asanti-IgE (for example omalizumab).

The present invention further relates to the combination of a compoundof the invention and another systemic or topically-appliedanti-inflammatory agent, such as thalidomide or a derivative thereof, aretinoid, dithranol or calcipotriol.

The present invention still further relates to the combination of acompound of the invention and combinations of aminosalicylates andsulfapyridine such as sulfasalazine, mesalazine, balsalazide, andolsalazine; and immunomodulatory agents such as the thiopurines, andcorticosteroids such as budesonide.

The present invention further relates to the combination of a compoundof the invention together with an antibacterial agent such as apenicillin derivative, a tetracycline, a macrolide, a beta-lactam, afluoroquinolone, metronidazole, an inhaled aminoglycoside; an antiviralagent including acyclovir, famciclovir, valaciclovir, ganciclovir,cidofovir, amantadine, rimantadine, ribavirin, zanamavir andoseltamavir; a protease inhibitor such as indinavir, nelfinavir,ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitorsuch as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; ora non-nucleoside reverse transcriptase inhibitor such as nevirapine orefavirenz.

The present invention still further relates to the combination of acompound of the invention and a cardiovascular agent such as a calciumchannel blocker, a beta-adrenoceptor blocker, an angiotensin-convertingenzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist; a lipidlowering agent such as a statin or a fibrate; a modulator of blood cellmorphology such as pentoxyfylline; thrombolytic, or an anticoagulantsuch as a platelet aggregation inhibitor.

The present invention further relates to the combination of a compoundof the invention and a CNS agent such as an antidepressant (such assertraline), an anti-Parkinsonian drug (such as deprenyl, L-dopa,ropinirole, pramipexole, a MAOB inhibitor such as selegine andrasagiline, a comP inhibitor such as tasmar, an A-2 inhibitor, adopamine reuptake inhibitor, an NMDA antagonist, a nicotine agonist, adopamine agonist or an inhibitor of neuronal nitric oxide synthase), oran anti-Alzheimer's drug such as donepezil, rivastigmine, tacrine, aCOX-2 inhibitor, propentofylline or metrifonate.

The present invention still further relates to the combination of acompound of the invention and an agent for the treatment of acute orchronic pain, such as a centrally or peripherally-acting analgesic (forexample an opioid or derivative thereof), carbamazepine, phenytoin,sodium valproate, amitryptiline or other anti-depressant agents,paracetamol, or a non-steroidal anti-inflammatory agent.

The present invention further relates to the combination of a compoundof the invention together with a parenterally or topically-applied(including inhaled) local anaesthetic agent such as lignocaine or aderivative thereof.

A compound of the present invention can also be used in combination withan anti-osteoporosis agent including a hormonal agent such asraloxifene, or a biphosphonate such as alendronate.

The present invention still further relates to the combination of acompound of the invention together with a: (i) tryptase inhibitor; (ii)platelet activating factor (PAF) antagonist; (iii) interleukinconverting enzyme (ICE) inhibitor; (iv) IMPDH inhibitor; (v) adhesionmolecule inhibitors including VLA-4 antagonist; (vi) cathepsin; (vii)kinase inhibitor such as an inhibitor of tyrosine kinase (such as Btk,Itk, Jak3 or MAP, for example Gefitinib or Imatinib mesylate), aserine/threonine kinase (such as an inhibitor of a MAP kinase such asp38, JNK, protein kinase A, B or C, or IKK), or a kinase involved incell cycle regulation (such as a cylin dependent kinase); (viii)glucose-6 phosphate dehydrogenase inhibitor; (ix) kinin-B1.- orB2.-receptor antagonist; (x) anti-gout agent, for example colchicine;(xi) xanthine oxidase inhibitor, for example allopurinol; (xii)uricosuric agent, for example probenecid, sulfinpyrazone orbenzbromarone; (xiii) growth hormone secretagogue; (xiv) transforminggrowth factor (TGFβ); (xv) platelet-derived growth factor (PDGF); (xvi)fibroblast growth factor for example basic fibroblast growth factor(bFGF); (xvii) granulocyte macrophage colony stimulating factor(GM-CSF); (xviii) capsaicin cream; (xix) tachykinin NK1 or NK3 receptorantagonist such as NKP-608C, SB-233412 (talnetant) or D-4418; (xx)elastase inhibitor such as UT-77 or ZD-0892; (xxi) TNF-alpha convertingenzyme inhibitor (TACE); (xxii) induced nitric oxide synthase (iNOS)inhibitor; (xxiii) chemoattractant receptor-homologous moleculeexpressed on TH2 cells, (such as a CRTH2 antagonist); (xxiv) inhibitorof P38; (xxv) agent modulating the function of Toll-like receptors(TLR), (xxvi) agent modulating the activity of purinergic receptors suchas P2X7; or (xxvii) inhibitor of transcription factor activation such asNFκB, API, or STATS.

A compound of the invention can also be used in combination with anexisting therapeutic agent for the treatment of cancer, for examplesuitable agents include:

(i) an antiproliferative/antineoplastic drug or a combination thereof,as used in medical oncology, such as an alkylating agent (for examplecis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan,chlorambucil, busulphan or a nitrosourea); an antimetabolite (forexample an antifolate such as a fluoropyrimidine like 5-fluorouracil ortegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea,gemcitabine or paclitaxel); an antitumour antibiotic (for example ananthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin,epirubicin, idarubicin, mitomycin-C, dactinomycin or mithramycin); anantimitotic agent (for example a vinca alkaloid such as vincristine,vinblastine, vindesine or vinorelbine, or a taxoid such as taxol ortaxotere); or a topoisomerase inhibitor (for example anepipodophyllotoxin such as etoposide, teniposide, amsacrine, topotecanor a camptothecin);(ii) a cytostatic agent such as an antioestrogen (for example tamoxifen,toremifene, raloxifene, droloxifene or iodoxyfene), an oestrogenreceptor down regulator (for example fulvestrant), an antiandrogen (forexample bicalutamide, flutamide, nilutamide or cyproterone acetate), aLHRH antagonist or LHRH agonist (for example goserelin, leuprorelin orbuserelin), a progestogen (for example megestrol acetate), an aromataseinhibitor (for example as anastrozole, letrozole, vorazole orexemestane) or an inhibitor of 5a-reductase such as finasteride;(iii) an agent which inhibits cancer cell invasion (for example ametalloproteinase inhibitor like marimastat or an inhibitor of urokinaseplasminogen activator receptor function);(iv) an inhibitor of growth factor function, for example: a growthfactor antibody (for example the anti-erbb2 antibody trastuzumab, or theanti-erbb1 antibody cetuximab [C225]), a farnesyl transferase inhibitor,a tyrosine kinase inhibitor or a serine/threonine kinase inhibitor, aninhibitor of the epidermal growth factor family (for example an EGFRfamily tyrosine kinase inhibitor such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine(gefitinib, AZD1839),N-(3-ethynylphenyI)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI-774) or6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine(Cl 1033)), an inhibitor of the platelet-derived growth factor family,or an inhibitor of the hepatocyte growth factor family;(v) an antiangiogenic agent such as one which inhibits the effects ofvascular endothelial growth factor (for example the anti-vascularendothelial cell growth factor antibody bevacizumab, a compounddisclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354), or acompound that works by another mechanism (for example linomide, aninhibitor of integrin αvβ3 function or an angiostatin);(vi) a vascular damaging agent such as combretastatin A4, or a compounddisclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO02/04434 or WO 02/08213;(vii) an agent used in antisense therapy, for example one directed toone of the targets listed above, such as ISIS 2503, an anti-rasantisense;(viii) an agent used in a gene therapy approach, for example approachesto replace aberrant genes such as aberrant p53 or aberrant BRCA1 orBRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such asthose using cytosine deaminase, thymidine kinase or a bacterialnitroreductase enzyme and approaches to increase patient tolerance tochemotherapy or radiotherapy such as multi-drug resistance gene therapy;or(ix) an agent used in an immunotherapeutic approach, for example ex-vivoand in-vivo approaches to increase the immunogenicity of patient tumourcells, such as transfection with cytokines such as interleukin 2,interleukin 4 or granulocyte-macrophage colony stimulating factor,approaches to decrease T-cell anergy, approaches using transfectedimmune cells such as cytokine-transfected dendritic cells, approachesusing cytokine-transfected tumour cell lines and approaches usinganti-idiotypic antibodies.

In a further embodiment the present invention provides a pharmaceuticalproduct comprising, in combination, a first active ingredient which is acompound of formula (I), (IA), (IB), (IC), (ID) or (IE) as hereinbeforedescribed, or a pharmaceutically acceptable salt thereof, and at leastone further active ingredient selected from:—

-   -   a phosphodiesterase inhibitor    -   a β2. adrenoceptor agonist    -   a modulator of chemokine receptor function    -   a protease inhibitor    -   a steroidal glucocorticoid receptor agonist    -   an anticholinergic agent, and a    -   a non-steroidal glucocorticoid receptor agonist.

The pharmaceutical product according to this embodiment may, forexample, be a pharmaceutical composition comprising the first andfurther active ingredients in admixture. Alternatively, thepharmaceutical product may, for example, comprise the first and furtheractive ingredients in separate pharmaceutical preparations suitable forsimultaneous, sequential or separate administration to a patient in needthereof. The pharmaceutical product of this embodiment is of particularuse in treating respiratory diseases such as asthma, COPD or rhinitis.

Examples of a phosphodiesterase inhibitor that may be used in thepharmaceutical product according to this embodiment include a PDE4inhibitor such as an inhibitor of the isoform PDE4D, a PDE3 inhibitorand a PDE5 inhibitor. Examples include the compounds

-   (Z)-3-(3,5-dichloro-4-pyridyl)-2-[4-(2-indanyloxy-5-methoxy-2-pyridyl]propenenitrile,-   N-[9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzodiazepin-3(R)-yl]pyridine-3-carboxamide    (C1-1044),-   3-(benzyloxy)-1-(4-fluorobenzyl)-N-[3-(methylsulphonyl)phenyl]-1H-indole-2-carboxamide,-   (1S-exo)-5-[3-(bicyclo[2.2.1]hept-2-yloxy)-4-methoxyphenyl]tetrahydro-2(1H)-pyrimidinone    (Atizoram),-   N-(3,5,dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-ol-2-oxoacetamide    (AWD-12-281),-   β-[3-(cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide    (CDC-801),-   N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzodiazepin-3(R)-yl]pyridine-4-carboxamide    (C1-1018),-   cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic    acid (Cilomilast),-   8-amino-1,3-bis(cyclopropylmethyl)xanthine (Cipamfylline),-   N-(2,5-dichloro-3-pyridinyl)-8-methoxy-5-quinolinecarboxamide    (D-4418),-   5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-iminothiazolidin-4-one    (Darbufelone),-   2-methyl-1-[2-(1-methylethyl)pyrazolo[1,5-a]pyridin-3-yl]-1-propanone    (Ibudilast),-   2-(2,4-dichlorophenylcarbonyI)-3-ureidobenzofuran-6-ylmethanesulphonate    (Lirimilast),-   (−)-(R)-5-(4-methoxy-3-propoxyphenyI)-5-methyloxazolidin-2-one    (Mesopram),-   (−)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-6-(4-diisopropylaminocarbonylphenyI)-benzo[c][1,6]naphthyridine    (Pumafentrine),-   3-(cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridyl)-4-(difluoromethoxy)benzamide    (Roflumilast),-   the N-oxide of Roflumilast,-   5,6-diethoxybenzo[b]thiophene-2-carboxylic acid (Tibenelast),-   2,3,6,7-tetrahydro-2-(mesitylimino)-9,10-dimethoxy-3-methyl-4H-pyrimido[6,1-a]isoquinolin-4-one    (trequinsin) and-   3-[[3-(cyclopentyloxy)-4-methoxyphenyl]-methyl]-N-ethyl-8-(1-methylethyl)-3H-purine-6-amine    (V-11294A).

Examples of a β₂-adrenoceptor agonist that may be used in thepharmaceutical product according to this embodiment includemetaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol (e.g.as sulphate), formoterol (e.g. as fumarate), salmeterol (e.g. asxinafoate), terbutaline, orciprenaline, bitolterol (e.g. as mesylate),pirbuterol or indacaterol. The β₂-adrenoceptor agonist of thisembodiment may be a long-acting β₂-agonists, for example salmeterol(e.g. as xinafoate), formoterol (e.g. as fumarate), bambuterol (e.g. ashydrochloride), carmoterol (TA 2005, chemically identified as2(1H)-Quinolone,8-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxy-phenyl)-1-methylethyl]-amino]ethyl]-monohydrochloride,[R—(R*,R*)] also identified by Chemical Abstract Service Registry Number137888-11-0 and disclosed in U.S. Pat. No. 4,579,854), indacaterol (CASno 312753-06-3; QAB-149), formanilide derivatives e.g.3-(4-{[6-({(2R)-2-[3-(formylamino)-4-hydroxyphenyl]-2-hydroxyethyl}amino)hexyl]oxy}-butyl)-benzenesulfonamideas disclosed in WO 2002/76933, benzenesulfonamide derivatives e.g.3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxy-methyl)phenyl]ethyl}amino)-hexyl]oxy}butyl)benzenesulfonamideas disclosed in WO 2002/88167, aryl aniline receptor agonists asdisclosed in WO 2003/042164 and WO 2005/025555, indole derivatives asdisclosed in WO 2004/032921, in US 2005/222144, compounds GSK 159797,GSK 159802, GSK 597901, GSK 642444 and GSK 678007.

Examples of a modulator of chemokine receptor function that may be usedin the pharmaceutical product according to this embodiment include aCCR1 receptor antagonist.

Examples of a protease inhibitor that may be used in the pharmaceuticalproduct according to this embodiment include an inhibitor of neutrophilelastase or an inhibitor of is MMP12.

Examples of a steroidal glucocorticoid receptor agonist that may be usedin the pharmaceutical product according to this embodiment includebudesonide, fluticasone (e.g. as propionate ester), mometasone (e.g. asfuroate ester), beclomethasone (e.g. as 17-propionate or17,21-dipropionate esters), ciclesonide, loteprednol (as e.g.etabonate), etiprednol (as e.g. dicloacetate), triamcinolone (e.g. asacetonide), flunisolide, zoticasone, flumoxonide, rofleponide,butixocort (e.g. as propionate ester), prednisolone, prednisone,tipredane, steroid esters e.g.6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17Iβ-carbothioicacid S-fluoromethyl ester,6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3S-yl) ester and6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17p-carbothioicacid S-fluoromethyl ester, steroid esters according to DE 4129535,steroids according to WO 2002/00679, WO 2005/041980, or steroids GSK870086, GSK 685698 and GSK 799943.

Examples of an anticholinergic agent that may be used in thepharmaceutical product according to this embodiment include for examplea muscarinic receptor antagonist (for example a M1, M2 or M3 antagonist,such as a M3 antagonist) for example ipratropium (e.g. as bromide),tiotropium (e.g. as bromide), oxitropium (e.g. as bromide), tolterodine,pirenzepine, telenzepine, glycopyrronium bromide (such asR,R-glycopyrronium bromide or a mixture of R,S- and S,R-glycopyrroniumbromide); mepensolate (e.g. as bromide), a quinuclidine derivative suchas3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azonia-bicyclo[2.2.2]octanebromide as disclosed in US 2003/0055080, quinuclidine derivatives asdisclosed in WO 2003/087096 and WO 2005/115467 and DE 10050995; or GSK656398 or GSK 961081.

Examples of a modulator of a non-steroidal glucocorticoid receptoragonist that may be used in the pharmaceutical product according to thisembodiment include those described in WO2006/046916.

EXPERIMENTAL METHODS

The following abbreviations have been used:

-   -   DMF N,N-dimethylformamide    -   DMSO dimethylsulphoxide    -   THF tetrahydrofuran    -   DMA N,N-dimethylacetamide    -   DCM dichloromethane.

In the examples the NMR spectra were measured on a Varian Unity Inovaspectrometer at a proton frequency of either 300 or 400 MHz. Reactionsthat were heated by microwave irradiation were pereperformed using a CEMDiscover Microwave. Examples having chiral centre might appear in NMR asa mixture of rotamers. The MS spectra were measured on either an Agilent1100 MSD G1946D spectrometer or a Hewlett Packard HP1100 MSD G1946Aspectrometer. Preparative HPLC separations were performed using a WatersSymmetry® or Xterra® column or Phenomenex Gemini® using 0.1% aqueoustrifluoroacetic acid: acetonitrile, 0.1% aqueous ammonia: acetonitrileor 0.1% ammonium acetate: acetonitrile as the eluent. SCX and NH₂ resinwere obtained from Varian Incorporated. Compound names were generatedusing the commercially available chemical naming software package IndexACDLABS 8.0.

Example 1

N-Cyclopropyl-3-[3-(2-fluoro-benzylamino)-2-oxo-2H-pyrazin-1-yl]-4-methyl-benzamide

a) 3-[(Cyanomethyl)amino]-4-methyl-benzoic acid, methyl ester

To a stirred solution of 3-amino-4-methyl-benzoic acid, methyl ester(10.0 g) in dry tetrahydrofuran was added N,N-diisopropylethylamine(12.6 mL) followed by the addition of bromoacetonitrile (5.1 mL). Thereaction was heated at reflux under an atmosphere of nitrogen withstirring for 12 h. Water was added and the mixture extracted with ethylacetate. The pooled organics were washed with brine, dried (MgSO₄),filtered and the solvent removed under reduced pressure to afford thesubtitle compound as a solid (12.4 g).

MS: APCI(+ve) 178 (M+H⁺).

¹H NMR δ (DMSO-d₆, 300 MHz) 7.31 (1H, dd), 7.23-7.17 (2H, m), 5.91 (1H,t), 4.33 (2H, d), 3.83 (3H, s), 2.17 (3H, s).

b) 3-(3,5-Dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methylester

To 3-[(cyanomethyl)amino]-4-methyl-benzoic acid, methyl ester (Example1a, 5.0 g) was added 1,2-dichlorobenzene (50 mL) and oxalyl bromide(11.5 mL). The reaction was heated at 100° C. for four h before thevolatiles were removed under reduced pressure and the residue azeotropedtwice with toluene. Purification (SiO₂ chromatography eluting withdichloromethane) afforded the subtitle compound as a solid (7.2 g).

MS: APCI(+ve) 401/403/405 (M+H⁺).

¹H NMR δ (DMSO-d₆, 400 MHz) 8.08 (1H, dd), 7.87 (1H, d), 7.46 (1H, d),7.29 (1H, s), 3.92 (3H, s), 2.25 (3H, s).

c) N-Cyclopropyl-3-[3-(2-fluoro-benzylamino)-2-oxo-2H-pyrazin-1-yl]-4-methyl-benzamide

To a stirred solution of3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methylester (Example 1 b, 0.1g) in tetrahydrofuran (1 mL) within a microwavevial was added triethylamine (38 μL) and 2-fluoro-benzenemethanamine (31μL). The reaction was stirred overnight before the addition ofcyclopropylamine (0.13 mL) and cyclopentylmagnesium bromide (2M indiethyl ether, 750 μL) dropwise. After stirring for 30 minutes, ethanol(2 mL) was added followed by the addition of ammonium formate (0.3 g)and 10% palladium on carbon (30 mg). The reaction mixture was heatedwithin a microwave for 60 minutes at 100° C. before being cooled to roomtemperature, filtered and washed with ethanol. The filtrate wasconcentrated in vacuo. Purification by preparative HPLC (Gemini column,0.1% ammonia: acetonitrile eluent) afforded the title compound as asolid (58 mg).

MS: APCI(+ve) 393 (M+H⁺).

¹H NMR δ (DMSO-d₆, 400 MHz) 8.44 (1H, d), 7.90-7.85 (2H, m), 7.76 (1H,d), 7.50 (1H, d), 7.35-7.26 (2H, m), 7.20-7.13 (2H, m), 6.82 (1H, d),6.72 (1H, d), 4.64 (1H, dd), 4.54 (1H, dd), 2.89-2.81 (1H, m), 2.12 (3H,s), 0.72-0.66 (2H, m), 0.58-0.53 (2H, m).

The following examples 2-49 (Table 1) were prepared and purified in asimilar manner to Example 1c.

Example 2

N-Cyclopropyl-4-methyl-3-[3-(4-methyl-1-piperazinyl)-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 3

N-Cyclopropyl-3-[3-[[3-(dimethylamino)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 4

N-Cyclopropyl-4-methyl-3-[3-[[3-(4-methyl-1-piperazinyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 5

N-Cyclopropyl-3-[3-[[2-(dimethylamino)ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 6

N-Cyclopropyl-4-methyl-3-[3-[[3-(4-morpholinyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 7

N-Cyclopropyl-4-methyl-3-[3-(methylamino)-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 8

N-Cyclopropyl-3-[3-[(3-methoxypropyl)amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 9

N-Cyclopropyl-4-methyl-3-[2-oxo-3-[[2-(2-pyridinyl)ethyl]amino]-1(2H)-pyrazinyl]-benzamide

Example 10

N-Cyclopropyl-4-methyl-3-[2-oxo-3-[(2-phenylethyl)amino]-1(2H)-pyrazinyl]-benzamide

Example 11

N-Cyclopropyl-4-methyl-3-[2-oxo-3-[(phenylmethyl)amino]-1(2H)-pyrazinyl]-benzamide

Example 12

N-Cyclopropyl-4-methyl-3-[2-oxo-3-(phenylamino)-1(2H)-pyrazinyl]-benzamide

Example 13

N-Cyclopropyl-3-[3-[[(3-methoxyphenyl)methyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 14

4-Methyl-3-[3-[[[4-(4-methyl-1-piperazinyl)phenyl]methyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-(1-methylpropyl)-benzamide

Example 15

N-Cyclopropyl-4-methyl-3-[2-oxo-3-[[(1R)-1-phenylethyl]amino]-1(2H)-pyrazinyl]-benzamide

Example 16

N-Cyclopropyl-4-methyl-3-[2-oxo-3-[[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl]amino]-1(2H)-pyrazinyl]-benzamide

Example 17

N-Cyclopropyl-3-[3-[[(1R)-2,3-dihydro-1H-inden-1-yl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 18

N-Cyclopropyl-4-methyl-3-[3-[(1-methyl-1-phenylethyl)amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 19

N-Cyclopropyl-4-methyl-3-[3-[methyl(phenylmethyl)amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 20

N-Cyclopropyl-3-[3-[[(4-methoxyphenyl)methyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 21

N-Cyclopropyl-4-methyl-3-[2-oxo-3-[[(1S)-1-phenylethyl]amino]-1(2H)-pyrazinyl]-benzamide

Example 22

N-Cyclopropyl-3-[3-[[(3-fluorophenyl)methyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 23

N-Cyclopropyl-4-methyl-3-[2-oxo-3-[(2-pyridinylmethyl)amino]-1(2H)-pyrazinyl]-benzamide

Example 24

N-Cyclopropyl-4-methyl-3-[2-oxo-3-[(3-pyridinylmethyl)amino]-1(2H)-pyrazinyl]-benzamide

Example 25

N-Cyclopropyl-4-methyl-3-[3-[[[4-(methylsulfonyl)phenyl]methyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 26

N-Cyclopropyl-3-[3-[[(2-methoxyphenyl)methyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 27

3-[3-[(1H-Benzimidazol-2-ylmethyl)amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide

Example 28

N-Cyclopropyl-4-methyl-3-[2-oxo-3-[(3-quinolinylmethyl)amino]-1(2H)-pyrazinyl]-benzamide

Example 29

N-Cyclopropyl-4-methyl-3-[2-oxo-3-[[(1,2,3,4-tetrahydro-3-quinolinyl)methyl]amino]-1(2H)-pyrazinyl]-benzamide

Example 30

N-Cyclopropyl-3-[3-(3,4-dihydro-2(1H)-isoquinolinyl)-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 31

N-Cyclopropyl-4-methyl-3-[2-oxo-3-[(2-thienylmethyl)amino]-1(2H)-pyrazinyl]-benzamide

Example 32

3-[3-[(1,3-Benzodioxol-5-ylmethyl)amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide

Example 33

N-Cyclopropyl-3-[3-[[(4-fluorophenyl)methyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 34

N-Cyclopropyl-4-methyl-3-[2-oxo-3-[[1-phenyl-2-(1-pyrrolidinyl)ethyl]amino]-1(2H)-pyrazinyl]-benzamide

Example 35

N-Cyclopropyl-4-methyl-3-[3-[[(1-methyl-4-phenyl-4-piperidinyl)methyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 36

N-Cyclopropyl-4-methyl-3-[2-oxo-3-[(3-phenylpropyl)amino]-1(2H)-pyrazinyl]-benzamide

Example 37

N-Cyclopropyl-3-[3-[[[4-(1,1-dimethylethyl)phenyl]methyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 38

N-Cyclopropyl-4-methyl-3-[2-oxo-3-[[(1R)-1-phenylpropyl]amino]-1(2H)-pyrazinyl]-benzamide

Example 39

N-Cyclopropyl-4-methyl-3-[3-[[(2-methylphenyl)methyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 40

N-Cyclopropyl-4-methyl-3-[3-[[[3-[(4-methyl-1-piperazinyl)methyl]phenyl]methyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 41

N-Cyclopropyl-4-methyl-3-[3-[[[2-[(4-methyl-1-piperazinyl)methyl]phenyl]methyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 42

N-Cyclopropyl-4-methyl-3-[3-[[(4-methylphenyl)methyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 43

3-[3-[(Cyclohexylmethyl)amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide

Example 44

3-[3-[([1,1-Biphenyl]-2-ylmethyl)amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide

Example 45

N-Cyclopropyl-4-methyl-3-[2-oxo-3-[[(4-phenoxyphenyl)methyl]amino]-1(2H)-pyrazinyl]-benzamide

Example 46

N-Cyclopropyl-4-methyl-3-[3-[[(3-methylphenyl)methyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 47

N-Cyclopropyl-4-methyl-3-[2-oxo-3-[[(1S,2R)-2-phenylcyclopropyl]amino]-1(2H)-pyrazinyl]-benzamide

Example 48

N-Cyclopropyl-4-methyl-3-[2-oxo-3-[[(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]amino]-1(2H)-pyrazinyl]-benzamide

Example 49

N-Cyclopropyl-3-[3-[(2,2-dimethylpropyl)amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

a) Where the amine was present as the salt extra triethylamine was used(38 μL).

b) Heating was required for the initial displacement (120° C. for 60minutes within a microwave) before cooling followed by the addition ofthe cyclopropylamine (0.13 mL) and cyclopentylmagnesium bromide (2M indiethyl ether, 750 μL) dropwise. c) Final purification by preparativeHPLC (Gemini column, 0.1% trifluroacetic acid:acetonitrile eluent)

TABLE 1

MS [M + H]⁺ Example R m/z ¹H NMR δ (DMSO-d₆)  2

368 8.43 (1H, d), 7.85 (1H, dd), 7.71 (1H, d), 7.47 (1H, d), 6.99 (1H,d), 6.97 (1H, d), 3.76-3.64 (4H, m), 2.88- 2.81 (1H, m), 2.39 (4H, t),2.19 (3H, s), 2.09 (3H, s), 0.71-0.66 (2H, m), 0.58-0.53 (2H, m)  3

370 8.44 (1H, d), 7.86 (1H, dd), 7.73 (1H, d), 7.50-7.44 (2H, m), 6.84(1H, d), 6.65 (1H, d), 3.43-3.26 (2H, m), 2.89- 2.81 (1H, m), 2.26 (2H,t), 2.12 (6H, s), 2.10 (3H, s), 1.69 (2H, quintet), 0.71-0.65 (2H, m),0.58-0.53 (2H, m)  4

425 8.44 (1H, d), 7.86 (1H, dd), 7.73 (1H, d), 7.52-7.46 (2H, m), 6.84(1H, d), 6.65 (1H, d), 3.43-3.27 (2H, m), 2.89- 2.81 (1H, m), 2.43-2.23(10H, m), 2.13 (3H, s), 2.10 (3H, s), 1.76-1.66 (2H, m), 0.72-0.66 (2H,m), 0.58- 0.53 (2H, m)  5

356 8.44 (1H, d), 7.86 (1H, dd), 7.73 (1H, d), 7.48 (1H, d), 7.08 (1H,t), 6.86 (1H, d), 6.68 (1H, d), 3.48-3.32 (2H, m), 2.89-2.80 (1H, m),2.45 (2H, td), 2.18 (6H, s), 2.10 (3H, s), 0.72-0.66 (2H, m), 0.58-0.53(2H, m)  6

412 8.44 (1H, d), 7.86 (1H, d), 7.73 (1H, s), 7.65 (1H, t), 7.49 (1H,d), 6.85 (1H, dd), 6.66 (1H, dd), 3.58 (4H, t), 3.46- 3.28 (2H, m),2.90-2.79 (1H, m), 2.41- 2.30 (6H, m), 2.10 (3H, s), 1.73 (2H, quintet),0.73-0.65 (2H, m), 0.60- 0.52 (2H, m)  7

299 8.44 (1H, d), 7.86 (1H, dd), 7.73 (1H, d), 7.48 (1H, d), 7.41-7.36(1H, m), 6.86 (1H, d), 6.66 (1 H, d), 2.88-2.81 (4H, m), 2.10 (3H, s),0.71-0.66 (2H, m), 0.58-0.53 (2H, m)  8

357 8.44 (1H, d), 7.86 (1H, dd), 7.74 (1H, d), 7.48 (1H, d), 7.35 (1H,t), 6.85 (1H, d), 6.66 (1H, d), 3.45-3.28 (4H, m), 3.23 (3H, s),2.89-2.81 (1H, m), 2.10 (3H, s), 1.81 (2H, quintet), 0.72-0.66 (2H, m),0.58-0.53 (2H, m)  9

390 8.51-8.48 (1H, m), 8.43 (1H, d), 7.86 (1H, dd), 7.74-7.68 (2H, m),7.48 (1H, d), 7.44 (1H, t), 7.29 (1H, d), 7.24- 7.20 (1H, m), 6.87 (1H,d), 6.69 (1H, d), 3.77-3.62 (2H, m), 3.09-3.01 (2H, m), 2.88-2.81 (1H,m), 2.10 (3H, s), 0.71-0.66 (2H, m), 0.58-0.53 (2H, m) 10

389 8.44 (1H, d), 7.86 (1 H, dd), 7.73 (1H, d), 7.48 (1H, d), 7.38-7.17(6H, m), 6.88 (1H, d), 6.68 (1H, d), 3.64-3.47 (2H, m), 2.94-2.80 (3H,m), 2.10 (3H, s), 0.72-0.65 (2H, m), 0.58-0.52 (2H, m) 11

375 8.43 (1H, d), 7.92 (1H, t), 7.87 (1H, dd), 7.75 (1H, d), 7.49 (1H,d), 7.36- 7.28 (4H, m), 7.25-7.20 (1H, m), 6.82 (1H, d), 6.70 (1H, d),4.59 (1H, dd), 4.48 (1H, dd), 2.89-2.81 (1H, m), 2.11 (3H, s), 0.71-0.66(2H, m), 0.58- 0.53 (2H, m) 12

361 9.27 (1H, s), 8.46 (1H, d), 8.02-7.98 (2H, m), 7.89 (1H, dd), 7.81(1H, d), 7.52 (1H, d), 7.32 (2H, t), 7.04-6.99 (2H, m), 6.96 (1H, d),2.89-2.82 (1H, m), 2.16 (3H, s), 0.72-0.67 (2H, m), 0.59-0.54 (2H, m) 13

405 8.43 (1H, d), 7.94-7.84 (2H, m), 7.75 (1H, d), 7.49 (1H, d), 7.22(1H, t), 6.92- 6.87 (2H, m), 6.84-6.77 (2H, m), 6.70 (1H, d), 4.56 (1H,dd), 4.45 (1H, dd), 3.73 (3H, s), 2.90-2.79 (1H, m), 2.11 (3H, s),0.73-0.65 (2H, m), 0.59- 0.51 (2H, m) 14

473 8.42 (1H, d), 7.86 (1H, dd), 7.76-7.72 (2H, m), 7.48 (1H, d), 7.19(2H, d), 6.89-6.85 (2H, m), 6.83 (1H, d), 6.68 (1H, d), 4.47 (1H, dd),4.37 (1H, dd), 3.08 (4H, t), 2.88-2.81 (1H, m), 2.43 (4H, t), 2.21 (3H,s), 2.10 (3H, s), 0.71- 0.65 (2H, m), 0.57-0.53 (2H, m) 15

389 8.47-8.37 (1H, m), 7.86 (1H, d), 7.74 (1H, d), 7.63-7.53 (1H, m),7.52- 7.45 (1H, m), 7.44-7.38 (2H, m), 7.36-7.27 (2H, m), 7.25-7.17 (1H,m), 6.83-6.78 (1H, m), 6.71-6.65 (1H, m), 5.15 (1H, quintet), 2.90-2.79(1H, m), 2.13 (1.5H, s), 2.08 (1.5H, s), 1.51 (3H, t), 0.73-0.63 (2H,m), 0.61- 0.50 (2H, m) 16

415 8.48-8.40 (1H, m), 7.87 (1H, d), 7.78 (1H, d), 7.49 (1H, d),7.25-7.08 (5H, m), 6.90 (1H, d), 6.75 (1H, d), 5.26 (1H, quintet),2.91-2.67 (3H, m), 2.15 (1.5H, s), 2.13 (1.5H, s), 2.03-1.84 (3H, m),1.83-1.69 (1H, m), 0.74- 0.64 (2H, m), 0.60-0.51 (2H, m) 17

401 8.51-8.40 (1H, m), 7.93-7.84 (1H, m), 7.83-7.74 (1H, m), 7.55-7.46(1H, m), 7.43-7.12 (5H, m), 6.96- 6.87 (1H, m), 6.81-6.73 (1H, m), 5.67-5.52 (1H, m), 3.09-2.94 (1H, m), 2.93-2.77 (2H, m), 2.60-2.40 (1H, m),2.21-2.00 (4H, m), 0.76-0.64 (2H, m), 0.62-0.53 (2H, m) 18^(b)

403 8.44 (1H, d), 7.87 (1H, dd), 7.76 (1H, d), 7.49 (1H, d), 7.41-7.36(2H, m), 7.33-7.27 (2H, m), 7.21-7.16 (1H, m), 6.93 (1H, s), 6.67 (2H,s), 2.89- 2.81 (1H, m), 2.12 (3H, s), 1.76 (3H, s), 1.72 (3H, s),0.72-0.66 (2H, m), 0.58-0.53 (2H, m) 19

389 8.45 (1H, d), 7.85 (1 H, dd), 7.74 (1H, d), 7.47 (1H, d), 7.36-7.30(2H, m), 7.27-7.21 (3H, m), 6.98 (1H, d), 6.91 (1H, d), 5.09 (1H, d),4.95 (1H, d), 3.03 (3H, s), 2.88-2.81 (1H, m), 2.09 (3H, s), 0.72-0.66(2H, m), 0.58- 0.54 (2H, m) 20

405 8.43 (1H, d), 7.86 (1H, dd), 7.82 (1H, t), 7.74 (1H, d), 7.49 (1H,d), 7.27 (2H, dd), 6.90-6.85 (2H, m), 6.83 (1H, d), 6.69 (1H, d), 4.51(1H, dd), 4.41 (1H, dd), 3.72 (3H, s), 2.88-2.81 (1H, m), 2.11 (3H, s),0.71-0.66 (2H, m), 0.57- 0.53 (2H, m) 21

389 8.46-8.37 (1H, m), 7.86 (1H, dd), 7.75-7.71 (1H, m), 7.62-7.53 (1H,m), 7.51-7.46 (1H, m), 7.44-7.38 (2H, m), 7.34-7.28 (2H, m), 7.24- 7.19(1H, m), 6.82-6.78 (1H, m), 6.70-6.65 (1H, m), 5.15 (1H, quintet),2.88-2.80 (1H, m), 2.12 (1.5H, s), 2.08 (1.5H, s), 1.51 (3H, t),0.72-0.65 (2H, m), 0.59-0.51 (2H, m) 22

393 8.43 (1H, d), 8.01 (1H, t), 7.87 (1H, dd), 7.76 (1H, d), 7.49 (1H,d), 7.36 (1H, td), 7.17 (1H, d), 7.15-7.11 (1H, m), 7.08-7.02 (1H, m),6.82 (1H, d), 6.71 (1H, d), 4.60 (1H, dd), 4.49 (1H, dd), 2.88-2.81 (1H,m), 2.12 (3H, s), 0.71-0.66 (2H, m), 0.58-0.53 (2H, m) 23

376 8.53-8.51 (1H, m), 8.45 (1H, d), 7.92 (1H, t), 7.87 (1H, dd),7.78-7.73 (2H, m), 7.50 (1H, d), 7.31 (1H, d), 7.28- 7.24 (1H, m), 6.82(1H, d), 6.74 (1H, d), 4.68 (1H, dd), 4.59 (1H, dd), 2.89- 2.82 (1H, m),2.13 (3H, s), 0.72-0.66 (2H, m), 0.59-0.53 (2H, m) 24

376 8.56 (1H, d), 8.46-8.40 (2H, m), 8.05 (1H, t), 7.89-7.84 (1H, m),7.77- 7.71 (2H, m), 7.49 (1H, d), 7.34 (1H, dd), 6.83 (1H, d), 6.72 (1H,d), 4.60 (1H, dd), 4.50 (1H, dd), 2.90-2.79 (1H, m), 2.11 (3H, s),0.73-0.65 (2H, m), 0.59-0.52 (2H, m) 25^(a)

453 8.44 (1H, d), 8.13 (1H, t), 7.87 (3H, d), 7.76 (1H, d), 7.57 (2H,d), 7.49 (1H, d), 6.81 (1H, d), 6.72 (1H, d), 4.68 (1H, dd), 4.57 (1H,dd), 3.19 (3H, s), 2.91-2.80 (1H, m), 2.12 (3H, s), 0.73- 0.65 (2H, m),0.59-0.52 (2H, m) 26

405 8.44 (1H, d), 7.87 (1H, dd), 7.77 (1H, d), 7.58 (1H, t), 7.50 (1H,d), 7.25- 7.20 (1H, m), 7.12 (1H, d), 6.99 (1H, d), 6.89 (1H, t), 6.81(1H, d), 6.70 (1H, d), 4.56 (1H, dd), 4.47 (1H, dd), 3.83 (3H, s),2.89-2.82 (1H, m), 2.13 (3H, s), 0.72-0.66 (2H, m), 0.58-0.54 (2H, m)27^(b)

415 12.19 (1H, s), 8.48 (1H, d), 7.92-7.85 (2H, m), 7.76 (1H, s),7.57-7.48 (2H, m), 7.47-7.41 (1H, m), 7.18-7.09 (2H, m), 6.84 (1H, dd),6.76 (1H, dd), 4.80 (1H, dd), 4.71 (1H, dd), 2.91- 2.81 (1H, m), 2.15(3H, s), 0.74-0.65 (2H, m), 0.60-0.53 (2H, m) 28^(a)

426 8.94 (1H, d), 8.42 (1H, d), 8.23 (1H, d), 8.16 (1H, t), 7.98 (2H,dd), 7.86 (1H, dd), 7.76-7.70 (2H, m), 7.62- 7.57 (1H, m), 7.49 (1H, d),6.84 (1H, d), 6.72 (1H, d), 4.78 (1H, dd), 4.69 (1H, dd), 2.88-2.81 (1H,m), 2.12 (3H, s), 0.71-0.65 (2H, m), 0.57- 0.53 (2H, m) 29

430 8.43 (1H, d), 7.87 (1H, dd), 7.75 (1H, t), 7.54-7.47 (2H, m),6.86-6.81 (3H, m), 6.68 (1H, d), 6.44-6.38 (2H, m), 5.62 (1H, s),3.43-3.27 (2H, m), 3.27-3.20 (1H, m), 2.91-2.81 (2H, m), 2.48-2.39 (1H,m), 2.31-2.21 (1H, m), 2.75-2.68 (1H, m), 2.12 (3H, s), 0.72-0.66 (2H,m), 0.58-0.53 (2H, m) 30

401 8.43 (1H, d), 7.86 (1H, dd), 7.73 (1H, d), 7.48 (1H, d), 7.18-7.15(4H, m), 7.02 (1H, d), 6.96 (1H, d), 4.86 (2H, dd), 4.09-3.98 (2H, m),2.91 (2H, t), 2.88-2.81 (1H, m), 2.11 (3H, s), 0.71- 0.66 (2H, m),0.57-0.53 (2H, m) 31

381 8.43 (1H, d), 7.93 (1H, t), 7.87 (1H, dd), 7.74 (1H, d), 7.49 (1H,d), 7.35 (1H, dd), 7.02 (1H, dd), 6.95 (1H, dd), 6.89 (1H, d), 6.73 (1H,d), 4.73 (1H, dd), 4.63 (1H, dd), 2.88-2.81 (1H, m), 2.10 (3H, s),0.71-0.65 (2H, m), 0.57-0.53 (2H, m) 32

419 8.42 (1H, d), 7.89-7.82 (2H, m), 7.74 (1H, d), 7.49 (1H, d), 6.92(1H, d), 6.86-6.79 (3H, m), 6.69 (1H, d), 5.97 (2H, d), 4.48 (1H, dd),4.38 (1H, dd), 2.88-2.81 (1H, m), 2.11 (3H, s), 0.71- 0.66 (2H, m),0.57-0.53 (2H, m) 33

393 8.43 (1H, d), 7.96 (1H, t), 7.86 (1H, dd), 7.75 (1H, d), 7.49 (1H,d), 7.40- 7.34 (2H, m), 7.17-7.10 (2H, m), 6.83 (1H, d), 6.70 (1H, d),4.56 (1H, dd), 4.45 (1H, dd), 2.88-2.81 (1H, m), 2.11 (3H, s), 0.72-0.66(2H, m), 0.58- 0.53 (2H, m) 34^(a)

458 8.44 (0.5H, d), 8.40 (0.5H, d), 7.86 (1H, dd), 7.75 (0.5H, d), 7.72(0.5H, d). 7.54-7.46 (2H, m), 7.43-7.38 (2H, m), 7.34-7.28 (2H, m),7.25- 7.19 (1H, m), 6.78-6.76 (1H, m), 6.69- 6.67 (1H, m), 5.10-5.01(1H, m), 3.07-2.99 (1H, m), 2.89-2.80 (1H, m), 2.70-2.57 (1H, m),2.52-2.44 (4H, m), 2.13 (1.5H, s), 2.08 (1.5H, s), 1.68-1.62 (4H, m),0.72-0.65 (2H, m), 0.58-0.51 (2H, m) 35

472 8.41 (1H, d), 7.85 (1H, dd), 7.70 (1H, d), 7.46 (1H, d), 7.43-7.32(4H, m), 7.21 (1H, t), 6.81 (1H, d), 6.66 (1H, d), 6.27-6.20 (1H, m),3.61 (1H, dd), 3.44 (1H, dd), 2.88-2.80 (1H, m), 2.54-2.43 (2H, m),2.16-2.03 (4H, m), 2.08 (3H, s), 2.05 (3H, s), 1.91- 1.82 (2H, m),0.71-0.65 (2H, m), 0.57- 0.52 (2H, m) 36

403 8.44 (1H, d), 7.86 (1H, dd), 7.74 (1H, d), 7.48 (1H, d), 7.40 (1H,t), 7.31- 7.25 (2H, m), 7.24-7.15 (3H, m), 6.84 (1H, d), 6.66 (1H, d),3.43-3.27 (2H, m), 2.89-2.81 (1H, m), 2.63 (2H, t), 2.10 (3H, s), 1.89(2H, quintet), 0.72- 0.66 (2H, m), 0.58-0.53 (2H, m) 37

431 8.42 (1H, d), 7.90-7.84 (2H, m), 7.74 (1H, d), 7.49 (1H, d),7.35-7.31 (2H, m), 7.28-7.24 (2H, m), 6.82 (1H, d), 6.69 (1H, d),4.57-4.51 (1H, m), 4.47- 4.41 (1H, m), 2.88-2.81 (1H, m), 2.11 (3H, s),1.26 (9H, s), 0.71-0.66 (2H, m), 0.58-0.53 (2H, m) 38

403 8.44 (0.5H, d), 8.38 (0.5H, d), 7.88- 7.84 (1H, m), 7.76 (0.5H, d),7.71 (0.5H, d), 7.61-7.56 (1H, m), 7.51- 7.46 (1H, m), 7.45-7.39 (2H,m), 7.34- 7.28 (2H, m), 7.24-7.19 (1H, m), 6.81-6.78 (1H, m), 6.68-6.65(1H, m), 4.91 (1H, dd), 2.89-2.79 (1H, m), 2.13 (1.5H, s), 2.06 (1.5H,s), 2.03- 1.90 (1H, m), 1.88-1.74 (1H, m), 0.86 (3H, td), 0.72-0.64 (2H,m), 0.59- 0.50 (2H, m) 39

389 8.44 (1H, d), 7.87 (1 H, dd), 7.81-7.74 (2H, m), 7.50 (1H, d),7.23-7.10 (4H, m), 6.82 (1H, d), 6.71 (1H, d), 4.61- 4.52 (1H, m),4.50-4.41 (1H, m), 2.90- 2.80 (1H, m), 2.33 (3H, s), 2.13 (3H, s),0.73-0.65 (2H, m), 0.59-0.52 (2H, m) 40^(a)

487 8.44 (1H, d), 7.90 (1H, t), 7.86 (1H, dd), 7.74 (1H, d), 7.49 (1H,d), 7.28- 7.18 (3H, m), 7.13 (1H, d), 6.82 (1H, d), 6.70 (1H, d), 4.56(1H, dd), 4.48 (1H, dd), 3.42 (2H, s), 2.88-2.81 (1H, m), 2.43-2.21 (8H,m), 2.13 (3H, s), 2.12 (3H, s), 0.71-0.66 (2H, m), 0.58- 0.53 (2H, m)41^(a)

487 8.42 (1H, d), 7.85 (1H, dd), 7.77 (1H, t), 7.74 (1H, d), 7.48 (1H,d), 7.37- 7.34 (1H, m), 7.27-7.18 (3H, m), 6.86 (1H, d), 6.69 (1H, d),4.69 (1H, dd), 4.59 (1H, dd), 3.60 (1H, d), 3.50 (1H, d), 2.88-2.81 (1H,m), 2.45-2.26 (8H, m), 2.10 (6H, s), 0.71-0.66 (2H, m), 0.57-0.52 (2H,m) 42

389 8.43 (1H, d), 7.88-7.82 (2H, m), 7.74 (1H, d), 7.49 (1H, d), 7.22(2H, d), 7.11 (2H, d), 6.82 (1H, d), 6.69 (1H, d), 4.53 (1H, dd), 4.43(1H, dd), 2.88- 2.81 (1H, m), 2.27 (3H, s), 2.11 (3H, s), 0.71-0.65 (2H,m), 0.58-0.53 (2H, m) 43

381 8.43 (1H, d), 7.86 (1H, dd), 7.74 (1H, d), 7.48 (1H, d), 7.30 (1H,t), 6.84 (1H, d), 6.65 (1H, d), 3.29-3.19 (1H, m), 3.17-3.06 (1H, m),2.90-2.80 (1H, m), 2.10 (3H, s), 1.75-1.55 (6H, m), 1.27-1.09 (3H, m),1.00-0.82 (2H, m), 0.73-0.65 (2H, m), 0.59-0.52 (2H, m) 44^(c)

451 8.47 (1H, d), 7.87 (1 H, dd), 7.77 (1H, d), 7.51-7.45 (3H, m),7.43-7.32 (7H, m), 7.25-7.21 (1H, m), 6.79 (1H, d), 6.76 (1H, d), 4.56(1H, dd), 4.48 (1H, dd), 2.89-2.81 (1H, m), 2.12 (3H, s), 0.72-0.67 (2H,m), 0.59- 0.54 (2H, m) 45

467 8.43 (1H, d), 7.92 (1H, t), 7.87 (1H, dd), 7.75 (1H, d), 7.49 (1H,d), 7.41- 7.34 (4H, m), 7.15-7.10 (1H, m), 7.01- 6.95 (4H, m), 6.84 (1H,d), 6.70 (1H, d), 4.57 (1H, dd), 4.46 (1H, dd), 2.89- 2.81 (1H, m), 2.12(3H, s), 0.72-0.66 (2H, m), 0.58-0.53 (2H, m) 46

389 8.43 (1H, d), 7.89-7.83 (2H, m), 7.75 (1H, d), 7.49 (1H, d), 7.19(1H, t), 7.15- 7.10 (2H, m), 7.04 (1H, d), 6.83 (1H, d), 6.69 (1H, d),4.55 (1H, dd), 4.44 (1H, dd), 2.88-2.81 (1H, m), 2.28 (3H, s), 2.11 (3H,s), 0.71-0.66 (2H, m), 0.58-0.53 (2H, m) 47^(a,b)

401 8.46-8.42 (1H, m), 7.86 (1H, dd), 7.74 (1H, d), 7.70 (1H, d), 7.49(1H, d), 7.30-7.24 (2H, m), 7.19-7.14 (3H, m), 6.86 (1H, d), 6.72 (1H,d), 3.04-2.98 (1H, m), 2.88-2.81 (1H, m), 2.11 (3H, s), 2.15-2.04 (1 H,m), 1.52-1.42 (1H, m), 1.25-1.15 (1H, m), 0.72-0.66 (2H, m), 0.58-0.53(2H, m) 48

415 8.47-8.41 (1H, m), 7.87 (1H, dd), 7.80-7.76 (1H, m), 7.49 (1H, d),7.25- 7.09 (5H, m), 6.91-6.89 (1H, m), 6.77-6.74 (1H, m), 5.31-5.22 (1H,m), 2.89-2.69 (3H, m), 2.15 (1.5H, s), 2.13 (1.5H, s), 2.03-1.85 (3H,m), 1.82-1.71 (1H, m), 0.72-0.66 (2H, m), 0.59-0.53 (2H, m) 49

355 8.44 (1H, d), 7.87 (1H, dd), 7.76 (1H, d), 7.49 (1H, d), 6.98 (1H,t), 6.84 (1H, d), 6.68 (1H, d), 3.35-3.28 (1H, m), 3.14 (1H, dd),2.89-2.81 (1H, m), 2.10 (3H, s), 0.91 (9H, s), 0.71-0.66 (2H, m),0.58-0.53 (2H, m)

Example 50

N-Cyclopropyl-4-methyl-3-[2-oxo-3-[[(2S)-2-phenylpropyl]amino]-1(2H)-pyrazinyl]benzamide

A mixture of 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoicacid, methyl ester (Example 1b, 0.1 g), N,N-diisopropylethylamnie (0.1mL), (S)-2-phenyl-1-propylamine (0.05 mL) and tetrahydrofuran (1 mL) wasstirred at room temperature overnight. Cyclopropylamine (0.2 mL) wasadded followed by the addition of cyclopentylmagnesium bromide (2M indiethyl ether, 0.8 mL). The mixture was stirred for 10 min., quenchedwith sat. NH₄Cl and extracted into ethyl acetate. The organic phaseconcentrated in vacuo. The residue was treated with ethanol (5 mL), wet10% palladium on carbon (45 mg) was added followed byN,N-diisopropylethylamnie (0.1 mL) and ammonium formate (0.4 g). Themixture was stirred under nitrogen atmosphere at 70° C. for 30 min. Themixture was filtered through a pad of Celite and the filtrateconcentrated in vacuo. Purification by preparative HPLC (Gemini column,0.1% ammonia: acetonitrile eluent) afforded the title compound as asolid (64 mg).

MS: APCI(+ve) 393 (M+H⁺).

¹H NMR δ (DMSO-d₅, 400 MHz) 8.42 (1H, t), 7.85 (1H, dd), 7.72 (1H, t,),7.47 (1H, d), 7.34-7.23 (4H, m), 7.23-7.13 (3H, m), 6.87 and 6.86 (1H,2×d), 6.68 and 6.67 (1H, 2×d), 3.59-3.38 (2H, m), 3.25-3.14 (1H, m),2.84 (1H, m), 2.08 and 2.06 (3H, 2×s), 1.22 (3H, d), 0.68 (2H, m), 0.55(2H, m).

The following examples 51-99 (Table 2) were prepared from3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methylester (Example 1 b) and the corresponding amines using the generalprocedure described for Example 50.

Example 51

[[3-[[[4-[5-[(Cyclopropylamino)carbonyl]-2-methylphenyl]-3,4-dihydro-3-oxopyrazinyl]amino]methyl]phenyl]methyl]-carbamicacid, 1,1-dimethylethyl ester

Example 52

[[4-[[[4-[5-[(Cyclopropylamino)carbonyl]-2-methylphenyl]-3,4-dihydro-3-oxopyrazinyl]amino]methyl]phenyl]methyl]-carbamicacid, 1,1-dimethylethyl ester

Example 53

N-Cyclopropyl-4-methyl-3-[2-oxo-3-(3-phenyl-1-piperazinyl)-1(2H)-pyrazinyl]-benzamide

Example 54

N-Cyclopropyl-4-methyl-3-[2-oxo-3-(3-phenyl-1-pyrrolidinyl)-1(2H)-pyrazinyl]-benzamide

Example 55

N-Cyclopropyl-3-[3-[[(2R)-2-hydroxy-2-phenylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 56

N-Cyclopropyl-3-[3-[[(2S)-2-hydroxy-2-phenylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 57

N-Cyclopropyl-4-methyl-3-[2-oxo-3-[[(2R)-2-phenylpropyl]amino]-1(2H)-pyrazinyl]-benzamide

Example 58

N-Cyclopropyl-4-methyl-3-[2-oxo-3-[[(2S)-2-phenylpropyl]amino]-1(2H)-pyrazinyl]-benzamide

Example 59

N-Cyclopropyl-4-methyl-3-[2-oxo-3-[3-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-1-piperidinyl]-1(2H)-pyrazinyl]-benzamide

Example 60

N-Cyclopropyl-4-methyl-3-[2-oxo-3-(3-phenyl-1-piperidinyl)-1(2H)-pyrazinyl]-benzamide

Example 61

N-Cyclopropyl-3-[3-[[2-(dimethylamino)-2-phenylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 62

N-Cyclopropyl-3-[3-[[2-(4-fluorophenyl)-1,1-dimethylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 63

N-Cyclopropyl-4-methyl-3-[2-oxo-3-[[2-phenyl-2-(1-pyrrolidinyl)ethyl]amino]-1(2H)-pyrazinyl]-benzamide

Example 64

N-Cyclopropyl-3-[3-[(2,3-dihydro-1H-inden-2-yl)amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 65

N-Cyclopropyl-3-[3-[(1,1-dimethyl-2-phenylethyl)amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 66

N-Cyclopropyl-4-methyl-3-[3-[methyl(2-phenylethyl)amino]-2-oxo-1(2H)-pyrazinyl]benzamide

Example 67

N-Cyclopropyl-4-methyl-3-[2-oxo-3-(2-phenyl-4-morpholinyl)-1(2H)-pyrazinyl]-benzamide

Example 68

N-Cyclopropyl-3-[3-[[(2-hydroxyphenyl)methyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 69

N-Cyclopropyl-3-[3-[[[3-[(cyclopropylamino)carbonyl]phenyl]methyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 70

N-Cyclopropyl-3-[3-[[2-(4-hydroxyphenyl)ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 71

N-Cyclopropyl-3-[3-[[2-(3-hydroxyphenyl)ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 72

N-Cyclopropyl-4-methyl-3-[3-[[2-(2-methylphenyl)ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 73

N-Cyclopropyl-4-methyl-3-[3-[[2-(3-methylphenyl)ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 74

N-Cyclopropyl-4-methyl-3-[3-[[2-(4-methylphenyl)ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 75

N-Cyclopropyl-3-[3-[2-[(2-fluorophenyl)methyl]-1-pyrrolidinyl]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 76

N-Cyclopropyl-4-methyl-3-[2-oxo-3-(1-piperidinyl)-1(2H)-pyrazinyl]-benzamide

Example 77

N-Cyclopropyl-4-methyl-3-[3-[[3-(4-morpholinyl)-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 78

N-Cyclopropyl-3-[3-[[(2-ethoxyphenyl)methyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 79

N-Cyclopropyl-4-methyl-3-[2-oxo-3-[[[2-(trifluoromethyl)phenyl]methyl]amino]-1(2H)-pyrazinyl]-benzamide

Example 80

N-Cyclopropyl-3-[3-[[(1S)-2-hydroxy-1-phenylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 81

N-Cyclopropyl-3-[3-[[(1R)-2-hydroxy-1-phenylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 82

N-Cyclopropyl-β-[[4-[5-[(cyclopropylamino)carbonyl]-2-methylphenyl]-3,4-dihydro-3-oxopyrazinyl]amino]-benzenepropanamide

Example 83

N-Cyclopropyl-3-[3-[(3-hydroxy-1-phenylpropyl)amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 84

N-Cyclopropyl-4-methyl-3-[3-[[(1R)-1-(1-naphthalenyl)ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 85

N-cyclopropyl-4-methyl-3-[2-oxo-3-[[(1S)-1-phenylpropyl]amino]-1(2H)-pyrazinyl]-benzamide

Example 86

N-Cyclopropyl-4-methyl-3-[2-oxo-3-(2-phenyl-1-pyrrolidinyl)-1(2H)-pyrazinyl]-benzamide

Example 87

(βR)-β-[[4-[5-[(Cyclopropylamino)carbonyl]-2-methylphenyl]-3,4-dihydro-3-oxopyrazinyl]amino]-benzenepropanoicacid, 1,1-dimethylethyl ester

Example 88

N-Cyclopropyl-3-[3-(cyclopropylamino)-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 89

(βR)—N-cyclopropyl-β-[[4-[5-[(cyclopropylamino)carbonyl]-2-methylphenyl]-3,4-dihydro-3-oxopyrazinyl]amino-benzenepropanamide

Example 90

N-Cyclopropyl-4-methyl-3-[2-oxo-3-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]-1(2H)-pyrazinyl]-benzamide

Example 91

N-Cyclopropyl-3-[3-[[(2,3-dihydro-1,4-benzodioxin-5-yl)methyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 92

N-Cyclopropyl-3-[3-[[(2,3-dimethylphenyl)methyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 93

N-Cyclopropyl-4-methyl-3-[2-oxo-3-[[[3-(trifluoromethyl)phenyl]methyl]amino]-1(2H)-pyrazinyl]-benzamide

Example 94

N-Cyclopropyl-4-methyl-3-[3-[2-(3-methylphenyl)-1-pipendinyl]-2-oxo-1(21-)-pyrazinyl]-benzamide

Example 95

N-Cyclopropyl-3-[3-[[(3,5-dimethylphenyl)methyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 96

N-Cyclopropyl-4-methyl-3-[3-[2-(3-methylphenyl)-1-pyrrolidinyl]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 97

N-Cyclopropyl-3-[3-[2-(2-methoxyphenyl)-1-pyrrolidinyl]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 98

N-Cyclopropyl-3-[3-[[(2,5-dimethylphenyl)methyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 99

3-[3-[[[3,5-Bis(trifluoromethyl)phenyl]methyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide

TABLE 2

MS Example R [M + H]⁺ m/z ¹H NMR δ (DMSO-d₆) 51

504 8.43 (1H, d), 7.87 (2H, m), 7.74 (1H, s), 7.49 (1H, d), 7.37 (1H,t), 7.25 (1H, t), 7.19 (2H, m), 7.09 (1H, d), 6.82 (1H, d), 6.69 (1H,d), 4.57 (1H, dd), 4.46 (1H, dd), 4.10 (2H, d), 2.84 (1H, m), 2.12 (3H,s), 0.68 (2H, m), 0.55 (2H, m) 52

504 8.43 (1H, d), 7.88 (2H, m), 7.75 (1H, s), 7.49 (1H, d), 7.35 (1H,m), 7.27 (2H, d), 7.17 (2H, d), 6.82 (1H, d), 6.69 (1H, d), 4.56 (1H,dd), 4.47 (1H, dd), 4.09 (1H, d), 2.85 (1H, m), 2.11 (3H, s), 0.67 (2H,m), 0.56 (2H, m)   53^(a)

430 7.72 and 7.70 (1H, 2 × dd), 7.58 and 7.54 (1H, 2 × d), 7.44 (2H, m),7.40 and 7.38 (1H, 2 × d), 7.33-7.23 (4H, m), 7.01 (1H, d), 6.57 (1H,d), 4.78 (1H, m), 3.98 (1H, d), 3.25-3.00 (3H, m), 2.93-2.79 (2H, m),2.22 and 2.18 (3H, 2 × s), 0.86 (2H, m), 0.59 (2H, m) 54

415 8.44 (1H, d), 7.84 (1H, dd), 7.71 (1H, t), 7.47 (1H, d), 7.36-7.28(3H, m), 7.29-7.19 (2H, m), 6.88 (1H, d), 6.72 and 6.71(1H, 2 × d),4.38-4.17 (1H, m), 4.08-3.91 (1H, m), 3.85- 3.56 (2H, m), 3.42 (1H, m),2.85 (1H, m), 2.35-2.20 (1H, m), 2.14 and 2.11 (3H, 2 × s), 1.98 (1H,m), 0.68 (2H, m), 0.56 (2H, m) 55

405 8.44 (1H, d), 7.86 (1H, dd), 7.73 (1H, s), 7.49 (1H, d), 7.42-7.31(4H, m), 7.30-7.22 (1H, m), 7.08 (1H, m), 6.86 and 6.85 (1H, 2 × d),6.71 and 6.70 (1H, 2 × d), 5.62 (1H, s), 4.87 (1H, m), 3.61 (1H, m),3.42 (1H, m), 2.84 (1H, m), 2.09 (3H, 2 × s), 0.69 (2H, m), 0.56 (2H, m)56

405 8.44 (1H, d), 7.86 (1H, dd), 7.73 (1H, s), 7.49 (1H, d), 7.42-7.31(4H, m), 7.30-7.22 (1H, m), 7.08 (1H, m), 6.86 and 6.85 (1H, 2 × d),6.71 and 6.70 (1H, 2 × d), 5.62 (1H, s), 4.87 (1H, m), 3.61 (1H, m),3.42 (1H, m), 2.84 (1H, m), 2.09 (3H, 2 × s), 0.70 (2H, m), 0.55 (2H, m)57

403 8.42 (1H, t), 7.85 (1H, dd), 7.72 (1H, t,), 7.47 (1H, d), 7.34-7.23(4H, m), 7.23-7.13 (2H, m), 6.87 and 6.86 (1H, 2 × d,), 6.68 and 6.67(1H, 2 × d), 3.59-3.38 (2H, m), 3.25-3.14 (1H, m), 2.84 (1H, m), 2.08and 2.06 (3H, 2 × s), 1.22 (3H, d), 0.68 (2H, m), 0.55 (2H, m)  58^(b)

403 8.42 (1H, t), 7.85 (1H, dd), 7.72 (1H, t,), 7.47 (1H, d), 7.34-7.23(4H, m), 7.23-7.13 (2H, m), 6.87 and 6.86 (1H, 2 × d,), 6.68 and 6.67(1H, 2 × d), 3.59-3.38 (2H, m), 3.25-3.14 (1H, m), 2.84 (1H, m), 2.08and 2.06 (3H, 2 × s), 1.22 (3H, d), 0.68 (2H, m), 0.55 (2H, m) 59

542 8.44 (1H, br), 7.85 (1H, dd), 7.73 and 7.71 (1H, 2 × d), 7.48 and7.36 (1H, 2 × d), 7.17 (2H, dd), 6.99 (1H, d), 6.95 and 6.94 (1H, 2 ×d), 6.87 (2H, dd), 4.69 (2H, m), 4.02 (2H, t), 2.92-2.69 (9H, m), 2.11and 2.08 (3H, 2 × s), 1.97-1.87 (1H, m), 1.83- 1.58 (8H, m), 0.69 (2H,m), 0.56 (2H, m) 60

429 8.43 (1H, br), 7.85 (1H, dd), 7.73 and 7.71 (1H, 2 × d), 7.48 and7.36 (1H, 2 × d), 7.35-7.17 (5H, m), 7.00 (1H, d), 6.95 and 6.94 (1H, 2× d), 4.72 (2H, m), 2.97-2.74 (4H, m), 2.11 and 2.08 (3H, s), 1.95 (1H,m), 1.84-1.59 (3H, m), 0.69 (2H, m), 0.56 (2H, m) 61

432 8.43 (1H, d), 7.85 (1H, dd), 7.71 (1H, d), 7.48 (1H, d), 7.40-7.23(5H, m), 6.86 (1H, d), 6.83 (1H, m), 6.69 (1H, d), 3.93-3.50 (3H, m),2.83 (1H, m), 2.12 (6H, s), 2.07 (3H, s), 0.69 (2H, m), 0.54 (2H, m) 62

435 8.44 (1H, d,), 7.86 (1H, dd), 7.75 (1H, d), 7.49 (1H, d), 7.14-7.03(4H, m), 6.95 (1H, d), 6.78 (1H, d), 6.16 (1H, s), 3.28 (1H, d), 3.06(1H, d), 2.85 (1H, m), 2.11 (3H, s), 1.44 (3H, s), 1.36 (3H, s), 0.69(2H, m), 0.55 (2H, m) 63

458 8.43 (1H, t), 7.85 (1H, dd), 7.70 (1H, s), 7.47 (1H, dd), 7.36-7.18(5H, m), 6.83 and 6.82 (1H, 2 × d), 6.72 (1H, m), 6.67 and 6.66 (1H, 2 ×d), 3.81 (1H, m), 3.65-3.51 (2H, m), 2.83 (1H, m), 2.40 (2H, m), 2.06and 2.04 (3H, 2 × s), 1.66 (4H, m), 0.68 (2H, m), 0.55 (2H, m) 64

401 8.43 (1H, d), 7.86 (1H, d), 7.75 (1H, s), 7.49 (1H, d), 7.41 (1H,d), 7.30- 7.07 (4H, m) 6.91 (1H, d), 6.73 (1H, d), 4.70 (1H, m),3.27-3.18 (2H, m), 3.12-2.92 (2H, m), 2.85 (1H, m), 2.12 (3H, s), 0.69(2H, m), 0.55 (2H, m) 65

417 8.45 (1H, s), 7.87 (1H, d), 7.76 (1H, s), 7.49 (1H, d), 7.31-7.16(3H, m), 7.09 (2H, d), 6.96 (1H, d), 6.77 (1H, d), 6.16 (1H, s), 3.04(1H, d), 2.91- 2.80 (1H, m), 2.11 (3H, s), 1.46 (3H, s), 1.37 (3H, s),0.75-0.64 (2H, m), 0.62-0.50 (2H, m) 66

403 8.45 (1H, d), 7.85 (1H, dd), 7.69 (1H, d), 7.47 (1H, d), 7.29-7.22(2H, m), 7.22-7.14 (3H, m), 6.93 (1H, d), 6.79 (1H, d), 4.11-4.01 (1H,m), 3.99-3.89 (1H, m), 3.11 (3H, s), 2.91-2.80 (3H, m), 2.08 (3H, s),0.74-0.65 (2H, m), 0.59-0.53 (2H, m) 67

431 8.44 (1H, t), 7.86 (1H, dd), 7.77 and 7.71(1H, 2 × d), 7.49 and 7.47(1H, 2 × d), 7.42-7.27 (5H, m), 7.05-7.01 (2H, s), 4.70 (1H, t), 4.61(1H, dt), 4.57-4.48 (1H, dd), 4.05 (1H, dd), 3.77 (1H, tt), 3.07 (1H,tt), 2.89- 2.79 (2H, m), 2.12 and 2.09 (3H, 2 × s), 0.73-0.65 (2H, m),0.60-0.52 (1H, m) 68

391 9.93 (1H, s), 8.42 (1H, d), 7.86 (1H, dd), 7.78-7.71 (2H, m), 7.49(1H, d), 7.13 (1H, dd), 7.09 (1H, dt), 6.84 (1H, d), 6.81 (1H, dd), 6.76(1H, dt), 6.72 (1H, d), 4.56-4.36 (2H, m), 2.89-2.79 (1H, m), 2.15 (3H,s), 0.73-0.64 (2H, m), 0.59-0.51 (2H, m) 69

458 8.42 (2H, m), 7.99 (1H, t), 7.87 (1H, dd), 7.78 (1H, s), 7.75 (1H,d), 7.66 (1H, d), 7.49 (1H, d), 7.46 (1H, d), 7.37 (1H, t), 6.82 (1H,d), 6.71 (1H, d), 4.62 (1H, dd), 4.51 (1H, dd), 2.90- 2.79 (2H, m), 2.16(3H, s), 0.73- 0.64 (4H, m), 0.60-0.52 (4H, m) 70

405 8.43 (1H, d), 7.86 (1H, dd), 7.73 (1H, d), 7.48 (1H, d), 7.27 (1H,t), 7.03 (2H, d), 6.87 (1H, d), 6.71-6.65 (3H, m), 3.58-3.41 (2H, m),2.90-2.70 (3H, m), 2.10 (3H, s), 0.69 (2H, m), 0.55 (2H, m) 71

405 9.26 (1H, s), 8.43 (1H, d), 7.86 (1H, dd), 7.73 (1H, d), 7.48 (1H,d), 7.32 (1H, t), 7.08 (1H, t), 6.88 (1H, d), 6.69 (1H, d), 6.67-6.63(2H, m), 6.60 (1H, m), 3.52 (2H, m), 2.90- 2.76 (3H, m), 2.10 (3H, s),0.69 (2H, m), 0.55 (2H, m) 72

403 8.44 (1H, d), 7.86 (1H, dd), 7.74 (1H, d), 7.49 (1H, d), 7.43 (1H,t), 7.20- 7.07 (4H, m), 6.88 (1H, d), 6.68 (1H, d), 3.59-3.44 (2H, m),2.96-2.79 (3H, m), 2.33 (3H, s), 2.10 (3H, s), 0.69 (2H, m), 0.56 (2H,m) 73

403 8.44 (1H, d), 7.86 (1H, dd), 7.73 (1H, d), 7.49 (1H, d), 7.34 (1H,t), 7.18 (1H, t), 7.03 (3H, m), 6.88 (1H, d), 6.69 (1H, d), 3.61-3.47(2H, m), 2.93-2.78 (3H, m), 2.28 (3H, s), 2.10 (3H, s), 0.69 (2H, m),0.55 (2H, m) 74

403 8.44 (1H, d), 7.86 (1H, dd), 7.73 (1H, d), 7.48 (1H, d), 7.30 (1H,t), 7.11 (4H, m), 6.88 (1H, d), 6.68 (1H, d), 3.62-3.45 (2H, m),2.91-2.77 (3H, m), 2.26 (3H, s), 2.09 (3H, s), 0.69 (2H, m), 0.55 (2H,m) 75

447 8.45 (1H, d), 7.86 (1H, m), 7.74 and 7.68 (1H, 2 × d), 7.48 (1H, d),7.38- 7.20 (2H, m), 7.18-7.06 (2H, m), 6.95 and 6.91 (1H, 2 × d), 6.76and 6.71 (1H, 2 × d), 4.95 (1H, br) 3.87- 3.73 (1H, br), 3.70-3.56 (1H,br), 3.02-2.71 (3H, m), 2.13 and 2.11 (3H, 2 × s), 1.92-1.75 (3H, m),1.69- 1.60 (1H, m), 0.69 (2H, m), 0.56 (2H, m) 76

353 8.43 (1H, d), 7.85 (1H, dd), 7.71 (1H, d), 7.47 (1H, d), 6.98 (1H,d), 6.92 (1H, d), 3.75-3.62 (4H, m), 2.85 (1H, m), 2.09 (3H, s),1.66-1.50 (6H, m), 0.69 (2H, m), 0.56 (2H, m) 77

488 8.52 and 8.38 (1H, 2 × d), 8.45 and 8.41 (1H, 2 × d), 7.87 (1H, dd),7.74 (1H, dd), 7.50 and 7.49 (1H, 2 × d), 7.40-7.16 (5H, m), 6.76 and6.75 (1H, 2 × d), 6.66 (1H, d), 5.16 (1H, m), 3.73-3.51 (4H, m), 2.84(1H, m), 2.44-2.18 (8H, m), 2.12 and 2.08 (3H, 2 × s), 0.69 (2H, m),0.55 (2H, m) 78

419 8.44 (1H, d), 7.87 (1H, dd), 7.76 (1H, d), 7.55 (1H, t), 7.49 (1H,d), 7.21 (1H, dt), 7.12 (1H, dd), 6.97 (1H, d), 6.88 (1H, dt), 6.82 (1H,d), 6.70 (1H, d), 4.61-4.44 (2H, m), 4.08 (2H, q), 2.85 (1H, m), 2.12(3H, s), 1.36 (1H, t), 0.69 (2H, m), 0.55 (2H, m) 79

443 8.46 (1H, d), 7.99 (1H, t), 7.88 (1H, dd), 7.79 (1H, d), 7.73 (1H,d), 7.64 (1H, t), 7.51 (1H, d), 7.49-7.42 (2H, m), 6.80 (1H, d), 6.75(1H, d), 4.80 (1H, d), 4.69 (1H, d), 2.86 (1H, m), 2.14 (3H, s), 0.70(2H, m), 0.56 (2H, m) 80

405 8.44 and 8.41 (1H, 2 × d), 7.87 (1H, dd), 7.75 and 7.73 (1H, 2 × d),7.52- 7.47 (1H, m), 7.46-7.28 (5H, m), 7.23 (1H, m), 6.79 and 6.77 (1H,2 × d), 6.70 and 6.69 (1H, 2 × d), 5.02 (2H, m), 3.73 (2H, m), 2.85 (1H,m), 2.13 and 2.09 (3H, 2 × s), 0.68 (2H, m), 0.55 (2H, m) 81

405 8.44 and 8.41 (1H, 2 × d), 7.87 (1H, dd), 7.75 and 7.73 (1H, 2 × d),7.52- 7.47 (1H, m), 7.46-7.28 (5H, m), 7.23 (1H, m), 6.79 and 6.77 (1H,2 × d), 6.70 and 6.69 (1H, 2 × d), 5.02 (2H, m), 3.73 (2H, m), 2.85 (1H,m), 2.13 and 2.09 (3H, 2 × s), 0.68 (2H, m), 0.55 (2H, m) 82

472 8.45 and 8.40 (1H, 2 × d), 7.96-7.88 (2H, m), 7.87 (1H, dd), 7.74and 7.72 (1H, 2 × d), 7.49 and 7.48 (1H, 2 × d), 7.39-7.27 (4H, m),7.25-7.19 (1H, m), 6.80 and 6.79 (1H, 2 × d), 6.69 and 6.69 (1H, 2 × d),5.43-5.34 (1H, m), 2.89-2.80 (1H, m), 2.70 (1H, dd), 2.61-2.49 (1H, m),2.13 and 2.08 (3H, 2 × s), 0.73-0.63 (2H, m), 0.59-0.50 (4H, m),0.30-0.15 (2H, m) 83

419 8.44 and 8.39 (1H, 2 × d), 7.90-7.77 (2H, m), 7.73 (1H, d), 7.49 and7.48 (1H, 2 × d), 7.43-7.35 (2H, m), 7.35- 7.26 (2H, m), 7.21 (1H, m),6.77 (1H, d), 6.66 and 6.65 (1H, 2 × d), 5.18 (1H, m), 4.61 (1H, m),3.48- 3.35 (2H, m), 2.85 (1H, m), 2.13 and 2.07 (3H, 2 × s), 2.15-1.87(2H, m), 0.74-0.62 (2H, m), 0.61-0.48 (2H, m) 84

439 8.45 and 8.41 (1H, 2 × d), 8.23 (1H, m), 7.91 (1H, d), 7.84 (1H, d),7.81 (1H, m), 7.78-7.69 (2H, m), 7.65- 7.44 (5H, m), 6.78 and 6.75 (1H,2 × d), 6.69 and 6.68 (1H, 2 × d), 5.95 (1H, m), 2.85 (1H, m), 2.14 and2.08 (3H, 2 × s), 1.64 and 1.63 (3H, 2 × d), 0.68 (2H, m), 0.55 (2H, m)85

403 8.44 and 8.38 (1H, 2 × d), 7.86 (1H, d), 7.71 and 7.61(1H, 2 × s),7.59 (1H, d), 7.49 (1H, m), 7.46-7.37 (2H, m), 7.31 (2H, t), 7.26-7.17(1H, m), 6.80 (1H, m), 6.67 (1H, m), 4.91 (1H, q), 2.84 (1H, m), 2.13(3H, 2 × s), 2.04-1.90 (1H, m), 1.88-1.73 (1H, m), 0.86 (3H, t), 0.68(2H, m), 0.55 (2H, m) 86

415 8.45-8.37 (1H, m), 7.84-7.77 (1H, m), 7.68 and 7.58 (1H, 2 × s),7.44 and 7.36 (1H, 2 × d), 7.29-7.23 (3H, m), 7.19-7.06 (3H, m),6.87-6.78 (1H, m), 6.71 and 6.68 (1H, d), 5.70 (1H, br), 4.10 (1H, br),3.83 (1H, br), 2.83 (1H, m), 2.41-2.27 (1H, m), 2.1 (1H, s), 1.93-1.64(6H, m), 0.68 (2H, m), 0.54 (2H, m) 87

489 8.47 and 8.39 (1H, 2 × d), 7.90-7.78 (2H, m), 7.72 and 7.71 (1H, 2 ×d), 7.51-7.41 (3H, m), 7.35-7.28 (2H, m), 7.26-7.20 (1H, m), 6.84 and6.83 (1H, 2 × d), 6.71 and 6.70 (1H, 2 × d), 5.54-5.40 (1H, m), 3.02-2.92 (1H, m), 2.89-2.77 (2H, m), 2.10 and 2.07 (3H, 2 × s), 1.28 and1.27 (9H, 2 × s), 0.68 (2H, m), 0.54 (2H, m) 88

325 8.43 (1H, d), 7.86 (1H, d), 7.73 (1H, s), 7.48 (1H, d), 7.40 (1H,d), 6.89 (1H, d), 6.72 (1H, d), 2.92-2.71 (2H, m), 2.10 (3H, s),0.78-0.45 (8H, m) 89

472 8.45 and 8.40 (1H, 2 × d), 7.96-7.88 (2H, m), 7.87 (1H, dd), 7.74and 7.72 (1H, 2 × d), 7.49 and 7.48 (1H, 2 × d), 7.39-7.27 (4H, m),7.25-7.19 (1H, m), 6.80 and 6.79 (1H, 2 × d), 6.69 and 6.69 (1H, 2 × d),5.43-5.34 (1H, m), 2.89-2.80 (1H, m), 2.70 (1H, dd), 2.61-2.49 (1H, m),2.13 and 2.08 (3H, 2 × s), 0.73-0.63 (2H, m), 0.59-0.50 (4H, m),0.30-0.15 (2H, m) 90

383 8.43 (1H, d), 7.86 (1H, dd), 7.74 (1H, d), 7.48 (1H, d), 7.40 (1H,t), 6.84 (1H, d), 6.66 (1H, d), 3.84 (2H, dd), 3.30-3.09 (4H, m), 2.84(1H, m), 2.10 (3H, s), 2.01-1.82 (1H, m), 1.57 (2H, d), 1.27-1.10 (2H,m), 0.69 (2H, m), 0.55 (2H, m) 91

433 8.44 (1H, d), 7.87 (1H, dd), 7.77 (1H, d), 7.59 (1H, t), 7.50 (1H,d), 6.82 (1H, d), 6.77-6.65 (4H, m), 4.55 (1H, dd), 4.44 (1H, dd),4.35-4.21 (4H, m), 2.85 (1H, m), 2.13 (3H, s), 0.69 (2H, m), 0.56 (2H,m) 92

403 8.44 (1H, d), 7.87 (1H, dd), 7.76 (1H, d), 7.63 (1H, t), 7.49 (1H,d), 7.09- 6.97 (3H, m), 6.82 (1H, d), 6.70 (1H, d), 4.58 (1H, dd), 4.47(1H, dd), 2.85 (1H, m), 2.25 (3H, s), 2.20 (3H, s), 2.12 (3H, s), 0.69(2H, m), 0.56 (2H, m) 93

443 8.43 (1H, d), 8.10 (1H, t), 7.87 (1H, dd), 7.75 (1H, d), 7.72-7.52(4H, m), 7.49 (1H, d), 6.82 (1H, d), 6.72 (1H, d), 4.66 (1H, dd), 4.56(1H, dd), 2.85 (1H, m), 2.11 (3H, s), 0.69 (2H, m), 0.55 (2H, m) 94

443 8.44 (1H, d), 7.84 (1H, d), 7.75 and 7.71 (1H, 2 × s), 7.46 (1H, t),7.27- 6.90 (5H, m), 6.16 and 6.05 (1H, 2 × br s), 4.47 (1H, t), 2.98(1H, m), 2.84 (1H, m), 2.38-2.22 (1H, m), 2.29 (3H, s), 2.13 and 2.02(3H, 2 × s), 1.97-1.80 (1H, m), 1.72-1.37 (4H, m), 0.69 (2H, m), 0.56(2H, m) 95

403 8.44 (1H, d), 7.86 (1H, dd), 7.79 (1H, t), 7.75 (1H, d), 7.49 (1H,d), 6.93 (2H, s), 6.86 (1H, s), 6.83 (1H, d), 6.69 (1H, d), 4.52 (1H,dd), 4.40 (1H, dd), 2.85 (1H, m), 2.25 (6H, d), 2.11 (3H, s), 0.69 (2H,m), 0.55 (2H, m) 96

429 8.45-8.37 (1H, m), 7.80 (1H, m), 7.68 and 7.59 (1H, 2 × s), 7.44 and7.37 (1H, 2 × d), 7.19-7.08 (1H, m), 7.01-6.76 (4H, m), 6.71 and 6.68(1H, 2 × d), 5.81-5.55 (1H, br), 4.18- 3.97 (1H, br), 3.93-3.72 (1H,br), 2.83 (1H, m), 2.29-2.21 (2H, m), 2.26 and 2.25 (3H, 2 × s), 2.08(1H, s), 1.92-1.66 (4H, m), 0.67 (2H, m), 0.54 (2H, m) 97

445 8.43-8.38 (1H, m), 7.84-7.77 (1H, m), 7.69 and 7.59 (1H, 2 × s),7.44 and 7.36 (1H, 2 × d), 7.19-7.11 (1H, m), 6.94 (1H, d), 6.87-6.77(3H, m), 6.68 and 6.66 (1H, 2 × d), 6.05- 5.89 (1H, br), 4.21-4.05 (1H,br), 3.80 (1H, br), 3.80 and 3.79 (3H, 2 × s), 2.84 (1H, m), 2.30-2.13(2H, m), 2.09 (1H, s), 1.93-1.81 (2H, m), 1.80-1.63 (4H, m), 0.67 (2H,m), 0.55 (2H, m) 98

403 8.45 (1H, d), 7.87 (1H, dd), 7.98 (1H, s), 7.77 (1H, d), 7.64 (1H,t), 7.50 (1H, d), 7.08-7.01 (2H, m), 6.95 (1H, d), 6.83 (1H, d), 6.71(1H, d), 4.53 (1H, dd), 4.42 (1H, dd), 2.85 (1H, m), 2.27 (3H, s), 2.22(3H, s), 2.12 (3H, s), 0.69 (2H, m), 0.56 (2H, m) 99

511 8.44 (1H, d), 8.20 (1H, t), 8.03 (2H, s), 7.87 (1H, dd), 7.76 (1H,d), 7.49 (1H, d), 6.82 (1H, d), 6.74 (1H, d), 4.80-4.57 (2H, m), 2.84(1H, m), 2.10 (3H, s), 0.69 (2H, m), 0.55 (2H, m) ^(a1)H NMR in CDCl₃^(b)Also included as example 50

Example 100

N-Cyclopropyl-4-methyl-3-[2-oxo-3-[[[2-[2-(1-pyrrolidinyl)ethoxy]phenyl]methyl]amino]-1(2H)-pyrazinyl]-benzamide

To a stirred solution of3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methylester (Example 1 b, 0.1 g) in tetrahydrofuran (2 mL) in a microwave vialwas added triethylamine (38 μL) and 2-(aminomethyl)-phenol (34 mg). Thereaction was stirred overnight before the solvent was removed. Theresidue was dissolved dry N,N-dimethylformamide (3 mL) and1-(2-chloroethyl)-pyrrolidine hydrochloride (211 mg) and cesiumcarbonate (808 mg) were added. The reaction mixture was heated at 80° C.for 12 h. The volatiles were removed under reduced pressure. Ethylacetate was added and the mixture washed with water and brine, thendried (MgSO₄), filtered and the solvent removed. Tetrahydrofuran (3 mL)was added to the vial followed by cyclopropylamine (0.15 mL) andcyclopentylmagnesium bromide (2M in diethyl ether, 1 mL) dropwise. Afterstirring for 30 minutes, ethanol (2 mL) was added followed by theaddition of ammonium is formate (0.3 g) and 10% palladium on carbon (30mg). The reaction mixture was heated within a microwave for 60 minutesat 100° C. before being cooled to room temperature, filtered and washedwith ethanol. The filtrate was concentrated in vacuo. Purification bypreparative HPLC (Gemini column, 0.1% ammonia: acetonitrile eluent)afforded the title compound as a solid (33 mg).

MS: APCI(+ve) 488 (M+H⁺).

¹H NMR δ (DMSO-d₆, 400 MHz) 8.44 (1H, d), 7.87 (1H, dd), 7.76 (1H, d),7.53 (1H, t), 7.49 (1H, d), 7.24-7.18 (1H, m), 7.14-7.11 (1H, m), 6.99(1H, d), 6.91-6.86 (1H, m), 6.81 (1H, d), 6.70 (1H, d), 4.57 (1H, dd),4.48 (1H, dd), 4.12 (2H, t), 2.89-2.81 (3H, m), 2.59-2.53 (4H, m), 2.12(3H, s), 1.71-1.65 (4H, m), 0.72-0.66 (2H, m), 0.58-0.53 (2H, m)

Example 101

N-Cyclopropyl-4-methyl-3-[2-oxo-3-[[(R)-phenyl-4-piperidinylmethyl]amino]-1(2H)-pyrazinyl]-benzamide,trifluoroacetate

a)4-[(R)-[[(R)-(1,1-Dimethylethyl)sulfinyl]amino]phenylmethyl]-1-piperidinecarboxylicacid, phenylmethyl ester

A mixture of 4-formyl-piperidine-1-carboxylic acid, benzyl ester (0.96g), (R)-2-methyl-2-propanesulfinamide (0.51 g), anhydrous copper(II)sulphate (1.5 g) and dichloromethane (20 mL) was stirred at roomtemperature for 48 h. Copper(II) sulphate was filtered off and thefiltrate concentrated. The residue was treated with dry dichloromethane(15 mL) and cooled to −78° C. A solution of phenylmagnesium bromide indiethyl ether (3M, 4 mL) was added dropwise. The mixture was slowlywarmed to 0° C., then quenched with sat. aqueous NH₄Cl solution. Themixture was stirred for 15 min and extracted into dichloromethane. Theorganic phase was dried (Na₂SO₄), filtered and concentrated in vacuo.The residue was purified (SiO₂ chromatography eluting with iso-hexane:ethyl acetate (0-100%)) to give the title compound (623 mg).

¹H NMR δ (CDCl₃, 400 MHz) 7.38-7.27 (8H, m), 7.22 (2H, m), 5.08 (2H, s),4.29-4.13 (3H, m), 3.41 (1H, d), 2.87-2.58 (2H, m), 2.04 (1H, m), 1.88(1H, m), 1.50 (1H, m), 1.23 (9H, s), 1.20-1.01 (2H, m).

b) 4-[(R)-Aminophenylmethyl]-1-piperidinecarboxylic acid, phenylmethylester

A mixture of4-[(R)-[[(R)-(1,1-dimethylethyl)sulfinyl]aminolphenylmethyl]-1-piperidinecarboxylicacid, phenylmethyl ester (0.59 g), methanol (5 mL) and hydrogen chloridein 1,4-dioxane (4M, 5 mL) was stirred at room temperature for 10 minutesthen concentrated in vacuo. The residue was diluted in dichloromethane(2 mL) and triturated with diethyl ether to afford the subtitle compoundas a solid (470 mg).

¹H NMR δ (DMSO-d₅, 400 MHz) 8.56 (2H, d), 7.51-7.26 (10H, m), 5.05 (2H,s), 4.13-4.01 (2H, m), 3.92 (1H, d), 2.90-2.59 (2H, m), 2.02 (1H, m),1.92 (1H, m), 1.18 (2H, m), 1.00 (1H, m).

c)N-Cyclopropyl-4-methyl-3-[2-oxo-3-[[(R)-phenyl-4-piperidinylmethyl]amino]-1(2H)-pyrazinyl]-benzamide

To a stirred solution of3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methylester (Example 1 b, 0.1 g) in tetrahydrofuran (1.5 mL) within amicrowave vial was added N,N-diisopropylethylamine (130 μL) and4-[(R)-aminophenylmethyl]-1-piperidinecarboxylic acid, phenylmethylester (98 mg). The reaction was heated at 110° C. for 60 minutes withina microwave. The reaction was cooled to room temperature before theaddition of cyclopropylamine (0.13 mL) and cyclopentylmagnesium bromide(2M in diethyl ether, 1 mL) dropwise. After stirring for 30 minutes,ethanol (1 mL) was added followed by ethyl acetate. The solvent waswashed with water, and brine, then dried (Na₂SO₄), filtered and thesolvent removed. The product was dissolved in t-butanol (2 mL) followedby the addition of 1,4-cyclohexadiene (1 mL) and 10% Pd on carbon (30mg). The reaction mixture was heated within a microwave at 120° C. for30 minutes, cooled to room temperature, filtered and purified bypreparative HPLC (Gemini column, 0.1% trifluoroacetic acid: acetonitrileeluent) to affordN-cyclopropyl-4-methyl-3-[2-oxo-3-[[(R)-phenyl-4-piperidinylmethyl]amino]-1(2H)-pyrazinyl]-benzamide(58 mg) and4-[(R)4-[4-[5-[(cyclopropylamino)carbonyl]-2-methylphenyl]-3,4-dihydro-3-oxopyrazinyl]amino]phenylmethyl]-1-piperidinecarboxylicacid, phenyl ester (19 mg).

MS: APCI(+ve) 458 (M+H⁺).

¹H NMR δ (DMSO-d₅, 400 MHz) 8.46 (0.5H, d), 8.36 (0.5H, d), 7.89-7.83(2H, m), 7.71 (1H, dd), 7.51-7.43 (3H, m), 7.37-7.31 (2H, m), 7.28-7.23(1H, m), 6.83-6.80 (1H, m), 6.72-6.68 (1H, m), 4.86-4.79 (1H, m),3.37-3.29 (1H, m), 3.24-3.17 (1H, m), 2.89-2.70 (3H, m), 2.29-2.18 (1H,m), 2.13 (1.5H, s), 2.10-2.00 (1H, m), 2.04 (1.5H, s), 1.45-1.22 (4H,m), 0.72-0.63 (2H, m), 0.58-0.49 (2H, m).

Example 102

4-[(R)[[4-[5-[(Cyclopropylamino)carbonyl]-2-methylphenyl]-3,4-dihydro-3-oxopyrazinyl]amino]phenylmethyl]-1-piperidinecarboxylicacid, phenylmethyl ester

To a stirred solution of3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid methyl ester(Example 1 b, 0.1g) in anhydrous THF (2 mL) within a microwave vial wasadded triethylamine (100 μL) and4-[(R)-aminophenylmethyl]-1-piperidinecarboxylic acid phenylmethyl ester(Example 101b, 98 mg). The reaction was heated within a microwave at120° C. for 60 minutes before cooling to room temperature and addingcyclopropylamine (150 μL) and cyclopentylmagnesium bromide (2M indiethyl ether, 0.75 mL) portionwise After stirring for 30 minutes,ethanol (2 mL) was added followed by the addition of ammonium formate(0.3 g) and 10% palladium on carbon (30 mg). The mixture was heatedwithin a microwave for 180 minutes at 100° C. before being cooled toroom temperature, filtered and washed with ethanol. The filtrate wasconcentrated in vacuo. Purification by preparative HPLC (Gemini column,0.1% ammonia: acetonitrile eluent) afforded the title compound (19 mg).

MS: APCI(+ve) 592 (M+H⁺).

¹H NMR δ (DMSO-d₆, 400 MHz) 8.46 (0.5H, d), 8.36 (0.5H, d), 7.86-7.82(1H, m), 7.80-7.71 (2H, m), 7.49-7.42 (3H, m), 7.36-7.29 (7H, m),7.26-7.20 (1H, m), 6.81-6.78 (1H, m), 6.67-6.63 (1H, m), 5.50 (2H, s),4.82-4.73 (1H, m), 4.12-4.0 (1H, m), 4.0-3.90 (1H, m), 2.90-2.75 (1H,m), 2.20-2.10 (1H, m), 2.13 (1.5H, s), 2.04 (1.5, s), 2.00-1.88 (1H, m),1.23-1.00 (4H, m), 0.7-0.64 (2H, m), 0.57-0.51 (2H, m).

Example 103

N-Cyclopropyl-4-methyl-3-[2-oxo-3-[[(S)-phenyl-4-piperidinylmethyl]amino]-1(2H)-pyrazinyl]-benzamidetrifluoroacetate

The title compound was prepared and purified in accordance with Example101 using (S)-2-methyl-2-propanesulfinamide.

MS: APCI(+ve) 458 (M+H⁺).

¹H NMR δ (DMSO-d₆, 400 MHz) 8.46 (0.5H, d), 8.36 (0.5H, d), 7.91-7.84(2H, m), 7.71 (1H, dd), 7.51-7.43 (3H, m), 7.37-7.30 (2H, m), 7.29-7.22(1H, m), 6.82-6.80 (1H, m), 6.72-6.68 (1H, m), 4.86-4.80 (1H, m),3.38-3.29 (1H, m), 3.25-3.17 (1H, m), 2.89-2.70 (3H, m), 2.30-2.18 (1H,m), 2.13 (1.5H, s), 2.04 (1.5H, s), 2.10-2.00 (1H, m), 1.43-1.21 (4H,m), 0.73-0.63 (2H, m), 0.58-0.49 (2H, m).

Example 104

3-[5-Cyano-2-oxo-3-[(phenylmethyl)amino]-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide

To a stirred solution of3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methylester (Example 1 b, 0.4 g) in tetrahydrofuran (2 mL) within a microwavevial was added N,N-diisopropylethylamine (330 μL) and benzenemethanamine(150 μL). The reaction was stirred overnight before the addition ofcyclopropylamine (0.5 mL) and cyclopentylmagnesium bromide (2M indiethyl ether, 3 mL) dropwise. The reaction was stirred for 30 minutesbefore ethanol (2 mL) was added followed by ammonium chloride. Thesolution was extracted with ethyl acetate and the organics were washedwith brine, dried (Na₂SO₄), filtered and the solvent removed to affordthe amide as a solid (543 mg). N,N-dimethylformamide (8 mL),tetrakis(triphenylphosphine)palladium(0) (50 mg) and zinc cyanide (421mg) were added and the reaction was heated within a microwave at 170° C.for 10 minutes. The reaction was cooled to room temperature. Water wasadded and the mixture extracted with ethyl acetate. The pooled organicswere washed with brine, dried (Na₂SO₄), filtered and the solvent removedto afford the title compound (570 mg).

MS: APCI(+ve) 400 (M+H⁺).

¹H NMR δ (DMSO-d₆, 400 MHz) 8.50 (1H, t), 8.42 (1H, d), 7.87 (1H, dd),7.81 (1H, d), 7.76 (1H, s), 7.50 (1H, d), 7.37-7.31 (4H, m), 7.29-7.23(1H, m), 4.62-4.55 (1H, m), 4.52-4.44 (1H, m), 2.88-2.81 (1H, m), 2.14(3H, s), 0.73-0.67 (2H, m), 0.58-0.53 (2H, m)

Example 105

N-Cyclopropyl-3-[5-[(dimethylamino)methyl]-2-oxo-3-[(phenylmethyl)amino]-1(2H)-pyrazinyl]-4-methyl-benzamide

To a stirred solution of3-[5-cyano-2-oxo-3-[(phenylmethyl)amino]-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide(Example 104, 100 mg) in methanol (2 mL) was added cobalt(II) chloride(119 mg) followed by sodium borohydride (95 mg) portionwise. After 15minutes 37% formaldehyde solution (0.5 mL) and sodiumtriacetoxyborohydride (150 mg) were added and the reaction stirredovernight. Water (5 mL) was added to the reaction and the mixture wasextracted with dichloromethane. The pooled organics were washed withbrine, dried (Na₂SO₄), filtered and the solvent removed. Purification bypreparative HPLC (Gemini column, 0.1% ammonia: acetonitrile eluent)afforded the title compound (24 mg).

MS: APCI(+ve) 432 (M+H⁺).

¹H NMR δ (DMSO-d₆, 400 MHz) 8.43 (1H, d), 7.88-7.81 (2H, m), 7.75 (1H,d), 7.48 (1H, d), 7.38-7.34 (2H, m), 7.33-7.28 (2H, m), 7.25-7.19 (1H,m), 6.56 (1H, s), 4.59 (1H, dd), 4.47 (1H, dd), 3.13 (2H, d), 2.88-2.80(1H, m), 2.15 (6H, s), 2.11 (3H, s), 0.71-0.65 (2H, m), 0.57-0.53 (2H,m)

Example 106

4-[5-[(Cyclopropylamino)carbonyl]-2-methylphenyl]-4,5-dihydro-5-oxo-6-[(phenylmethyl)amino]-2-pyrazinecarboxamide

To a stirred solution of3-[5-cyano-2-oxo-3-[(phenylmethyl)amino]-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide(Example 104, 100 mg) in methanol (1 mL) was added conc. ammoniasolution (1 mL) followed by 30% hydrogen peroxide solution (1 mL). After12 h, water was added and the mixture was extracted withdichloromethane. The pooled organics were washed with brine, dried(MgSO₄), filtered and the solvent removed. Purification by preparativeHPLC (Gemini column, 0.1% ammonia: acetonitrile eluent) afforded thetitle compound (31 mg).

MS: APCI(+ve) 418 (M+H⁺).

¹H NMR δ (DMSO-d₆, 400 MHz) 8.44 (1H, d), 8.19 (1H, t), 7.86 (1H, dd),7.77 (1H, d), 7.58 (1H, d), 7.49 (1H, d), 7.45-7.40 (3H, m), 7.32 (2H,td), 7.26-7.21 (2H, m), 4.72 (1H, dd), 4.57 (1H, dd), 2.88-2.80 (1H, m),2.11 (3H, s), 0.71-0.66 (2H, m), 0.57-0.53 (2H, m).

Example 107

3-[5-Chloro-3-(4-methyl-1-piperazinyl)-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide

a) 3-(3,5-Dichloro-2-oxo-1(2H)-pyrazinyl)-4-methyl-benzoic acid, methylester

To 3-[(cyanomethyl)amino]-4-methyl-benzoic acid, methyl ester (Example1a, 1.2 g) was added 1,2-dichlorobenzene (20 mL) and oxalyl chloride (3mL). The reaction was heated at 100° C. for four h before the volatileswere removed under reduced pressure. The residue was purified (SiO₂chromatography eluting with dichloromethane) to afford the subtitlecompound (800 mg).

MS: APCI(+ve) 313 (M+H±).

b)3-[5-Chloro-3-(4-methyl-1-piperazinyl)-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoicacid, methyl ester

To a stirred solution of3-(3,5-dichloro-2-oxo-1(2H)-pyrazinyl)-4-methyl-benzoic acid, methylester, (Example 107a, 250 mg) in acetonitrile (5 mL) was added1-methylpiperazine (0.2 mL). After 12 h, the reaction mixture wasconcentrated in vacuo. The residue was diluted with dichloromethane,washed with sat. aqueous NaHCO₃, dried (MgSO₄), filtered and the solventremoved to afford the subtitle compound.

MS: APCI(+ve) 377 (M+H⁺).

c)3-[5-Chloro-3-(4-methyl-1-piperazinyl)-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide

To a stirred solution of3-[5-chloro-3-(4-methyl-1-piperazinyl)-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoicacid, methyl ester (Example 107b) in tetrahydrofuran (6 mL) undernitrogen was added cyclopropylamine (0.15 mL) followed byiso-propylmagnesium chloride (2M in tetrahydrofuran, 0.8 mL),portionwise. After 1 h, sat. aqueous NH₄Cl was added and the mixtureextracted into ethyl acetate. The combined organic extracts were washedwith brine, dried (MgSO₄), filtered and the solvent removed in vacuo.Purification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent) afforded the title compound (35 mg).

MS: APCI(+ve) 402 (M+H⁺).

¹H NMR δ (DMSO-d₅, 400 MHz) 8.42 (1H, d), 7.84 (1H, dd), 7.73 (1H, d),7.46 (1H, d), 7.18 (1H, s), 3.88-3.74 (4H, m), 2.88-2.80 (1H, m),2.43-2.36 (4H, m), 2.19 (3H, s), 2.12 (3H, s), 0.72-0.66 (2H, m),0.58-0.53 (2H, m).

Example 108

3-[5-Chloro-3-[[3-(dimethylamino)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide

To a stirred solution of3-(3,5-dichloro-2-oxo-1(2H)-pyrazinyl)-4-methyl-benzoic acid, methylester (Example 107a, 200 mg) in tetrahydrofuran (3 mL) was addedN,N-dimethyl-1,3-propanediamine (90 μL) and the mixture was stirred atroom temperature for 12 h. Cyclopropylamine (220 μL) was added followedby the addition of iso-propylmagnesium chloride (2M in tetrahydrofuran,1 mL) portionwise. The reaction mixture was stirred for 60 minutes andiso-propylmagnesium chloride (2M in tetrahydrofuran, 1 mL) was added.The mixture was stirred for an additional 30 minutes and sat. aqueousNH₄Cl was added. The aqueous solution was extracted with ethyl acetate.The pooled organic was washed with brine and dried (MgSO₄), filtered andthe solvent removed. Purification by preparative HPLC (Gemini column,0.1% ammonia: acetonitrile eluent) gave the title compound (149 mg).

MS: APCI(+ve) 404 (M+H⁺).

¹H NMR δ (DMSO-d₆, 400 MHz) 8.43 (1H, d), 8.03 (1H, t), 7.85 (1H, dd),7.76 (1H, d), 7.48 (1H, d), 6.89 (1H, s), 3.41-3.26 (2H, m), 2.89-2.81(1H, m), 2.27 (2H, t), 2.14 (6H, s), 2.12 (3H, s), 1.71 (2H, quintet),0.72-0.66 (2H, m), 0.58-0.53 (2H, m)

Example 109

3-[5-Chloro-2-oxo-3-[(phenylmethyl)amino]-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide

To a stirred solution of3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methylester (Example 1 b, 0.2 g) in tetrahydrofuran (3 mL) within a microwavevial was added triethylamine (76 μL) and benzylamine (64 mg). Thereaction was stirred overnight before the addition of cyclopropylamine(0.22 mL) and iso-propylmagnesium chloride (2M in tetrahydrofuran, 1.5mL) dropwise. After stirring for 30 minutes, ethanol (2 mL), formic acid(0.4 mL) and 10% palladium on carbon (30 mg) were added. The reactionmixture was heated within a microwave for 60 minutes at 110° C. beforebeing cooled to room temperature, filtered and washed with ethanol. Thefiltrate was concentrated in vacuo. Purification by preparative HPLC(Gemini column, 0.1% ammonia: acetonitrile eluent) afforded the titlecompound (80 mg).

MS: APCI(+ve) 409 (M+H⁺).

¹H NMR δ (DMSO-d₆, 400 MHz) 8.47-8.39 (2H, m), 7.86 (1H, dd), 7.78 (1H,d), 7.48 (1H, d), 7.37-7.31 (4H, m), 7.28-7.22 (1H, m), 6.94 (1H, s),4.52 (2H, ddd), 2.88-2.80 (1H, m), 2.13 (3H, s), 0.72-0.66 (2H, m),0.57-0.53 (2H, m).

Example 110

3-[5-Chloro-2-oxo-3-[(2-phenylethyl)amino]-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide

The title compound was prepared and purified in accordance to Example109.

MS: APCI(+ve) 423 (M+H⁺).

¹H NMR δ (DMSO-d₅, 300 MHz) 8.43 (1H, d), 7.94-7.82 (2H, m), 7.76 (1H,s), 7.48 (1H, d), 7.35-7.18 (5H, m), 6.92 (1H, d), 3.64-3.46 (2H, m),2.96-2.80 (3H, m), 2.12 (3H, s), 0.74-0.63 (2H, m), 0.61-0.50 (2H, m).

Example 111

N-Methoxy-4-methyl-3-[3-[[[2-[(4-methyl-1-piperazinyl)methyl]phenyl]methyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

To a stirred solution of3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methylester (Example 1 b, 0.1 g) in tetrahydrofuran (2 mL) in a microwave vialwas added triethylamine (250 μL) and2-[(4-methyl-1-piperazinyl)methyl]-benzenemethanamine (90 mg). Thereaction was stirred overnight before the addition ofO-methylhydroxylamine hydrochloride (83 mg) and cyclopentylmagnesiumbromide (2M in diethyl ether, 2 mL) dropwise. After stirring for 60minutes, ethanol (2 mL) was added followed by the addition of ammoniumformate (0.4 g) and 10% palladium on carbon (40 mg). The reactionmixture was heated within a microwave for 30 minutes at 100° C. beforebeing cooled to room temperature, filtered and washed with ethanol. Thefiltrate was concentrated in vacuo. Purification by preparative HPLC(Gemini column, 0.1% trifluroacetic acid: acetonitrile eluent) affordedthe title compound (13 mg).

MS: APCI(+ve) 477 (M+Ht).

¹H NMR δ (DMSO-d₅, 400 MHz) 7.77 (1H, d), 7.67 (1H, s), 7.51 (1H, d),7.41 (1H, d), 7.33-7.27 (3H, m), 6.90 (1H, d), 6.75 (1H, d), 4.72 (1H,d), 4.62 (1H, d), 3.80-3.69 (2H, m), 3.69 (3H, s), 3.44-3.25 (4H, m),2.70 (3H, s), 2.50-2.35 (2H, m), 2.12 (3H, s).

Example 112

N-Methoxy-4-methyl-3-[3-[(1-methyl-1-phenylethyl)amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

To a stirred solution of3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methylester (Example 1 b, 0.1 g) in tetrahydrofuran (1 mL) within a microwavevial was added triethylamine (38 μL) and α,α-dimethyl-benzenemethanamine(74 mg). The reaction was heated within a microwave for 120 minutes at120° C. before being cooled to room temperature and the addition ofO-methylhydroxylamine hydrochloride (83 mg) and cyclopentylmagnesiumbromide (2M in diethyl ether, 2 mL) added dropwise. After stirring for30 minutes, ethanol (2 mL) was added followed by the addition ofammonium formate (0.4 g) and 10% palladium on carbon (40 mg). Thereaction mixture was heated within a microwave for 120 minutes at 80° C.before being cooled to room temperature, filtered and washed withethanol. The filtrate was concentrated in vacuo. Purification bypreparative HPLC (Gemini column, 0.1% ammonia: acetonitrile eluent)afforded the title compound as a solid (40 mg).

MS: APCI(+ve) 393 (M+H+).

¹H NMR δ (DMSO-d₅, 400 MHz) 11.78 (1H, s), 7.79 (1H, dd), 7.67 (1H, s),7.52 (1H, d), 7.41-7.37 (2H, m), 7.34-7.27 (2H, m), 7.21-7.16 (1H, m),6.93 (1H, s), 6.67 (2H, s), 3.70 (3H, s), 2.13 (3H, s), 1.76 (3H, s),1.73 (3H, s).

Example 113

N-Methoxy-4-methyl-3-[2-oxo-3-[[(1R)-1-phenylpropyl]amino]-1(2H)-pyrazinyl]-benzamide,trifluroacetate

To a stirred solution of3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methylester (Example 1b, 0.2 g) in tetrahydrofuran (2 mL) within a microwavevial was added triethylamine (80 μL) and α-ethyl-(αR)-benzenemethanamine(74 mg). The reaction was stirred for 12 h and ammonium formate (0.3 g),10% palladium on carbon (30 mg) and ethanol (3 mL) were added. Thereaction mixture was heated within a microwave for 30 minutes at 70° C.before being cooled to room temperature, filtered and washed withethanol. The filtrate was concentrated in vacuo. The residue was treatedwith ethyl acetate and washed with water. The organic phase wasconcentrated and the residue taken up in tetrahydrofuran (5 mL) andO-methylhydroxylamine hydrochloride (166 mg) was added followed bydropwise addition of cyclopentylmagnesium bromide (2M in diethyl ether,4 mL). After 30 min. sat. aqueous NH₄Cl was added and the mixtureextracted with ethyl acetate. The organic phase was concentrated invacuo. Purification by preparative HPLC (Gemini column, 0.1%trifluroacetic acid: acetonitrile eluent) afforded the title compound asa solid (137 mg).

MS: APCI(+ve) 393 (M+H⁺).

¹H NMR δ (DMSO-d₅, 400 MHz) 11.84-11.71 (1H, m), 7.78 (1H, d), 7.67 (1H,d), 7.52 (2H, t), 7.46-7.41 (2H, m), 7.35-7.30 (2H, m), 7.26-7.21 (1H,m), 6.82-6.79 (1H, m), 6.73-6.70 (1H, m), 4.90 (1H, q), 3.71 (1.5H, s),3.68 (1.5H, s), 2.15 (1.5H, s), 2.09 (1.5H, s), 2.03-1.95 (1H, m),1.90-1.78 (1H, m), 0.87 (3H, t).

Example 114

N-Cyclopropyl-4-methyl-3-(2-oxo-3-phenyl-1(2H)-pyrazinyl)-benzamide

To a stirred solution of3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methylester (Example 1 b, 0.2 g) in tetrahydrofuran (2 mL) and water (1 mL)was added phenylboronic acid (61 mg), sodium carbonate (105 mg) andtetrakis(triphenylphosphine)palladium(0) (20 mg). The reagents wereheated within a microwave at 120° C. for 30 minutes. The reaction wascooled to room temperature, phenylboronic acid (30 mg) added and thenheated within a microwave at 80° C. for 40 minutes. The reaction wascooled to room temperature followed by the addition of ammonium formate(0.4 g), 10% palladium on carbon (30 mg), formic acid (0.2 mL) andethanol (1 mL). The reaction mixture was heated within a microwave for60 minutes at 100° C. before being cooled to room temperature. Water wasadded and the mixture extracted with ethyl acetate. The pooled organicwere washed with water, dried (Na₂SO₄), filtered and concentrated. Theproduct was taken up in tetrahydrofuran (4 mL) followed by the additionof cyclopropylamine (0.22 mL) and cyclopentylmagnesium bromide (2M indiethyl ether, 1.5 mL) dropwise. After stirring for 60 minutes, ethanol(2 mL) was added and the mixture was purified by preparative HPLC(Gemini column, 0.1% ammonia: acetonitrile eluent) to afford the titlecompound as a solid (20 mg).

MS: APCI(+ve) 346 (M+H⁺).

¹H NMR δ (DMSO-d₆, 400 MHz) 8.46 (1H, d), 8.30-8.24 (2H, m), 7.90 (1H,dd), 7.83 (1H, d), 7.66 (1H, d), 7.60 (1H, d), 7.53 (1H, d), 7.48-7.44(3H, m), 2.89-2.82 (1H, m), 2.16 (3H, s), 0.72-0.67 (2H, m), 0.59-0.54(2H, m).

Example 115

N-Ethyl-4-methyl-3-[2-oxo-3-[(phenylmethyl)amino]-1(2H)-pyrazinyl]-benzamide

The title compound was prepared and purified in accordance to Example 1cusing benzylamine and ethylamine (2M in tetrahydrofuran).

MS: APCI(+ve) 363 (M+H⁺).

¹H NMR δ (DMSO-d₆, 400 MHz) 8.47 (1H, t), 7.92 (1H, t), 7.88 (1H, dd),7.77 (1H, d), 7.50 (1H, d), 7.36-7.29 (4H, m), 7.25-7.20 (1H, m), 6.83(1H, d), 6.71 (1H, d), 4.59 (1H, dd), 4.49 (1H, dd), 3.30-3.24 (2H, m),2.12 (3H, s), 1.11 (3H, t).

Example 116

N-Cyclopropyl-4-methyl-3-(2-oxo-3-phenoxy-1(2H)-pyrazinyl)-benzamide

A mixture of 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoicacid, methyl ester (Example 1b, 204 mg), phenol (206 mg),N,N-diisopropylethylamine (0.3 mL) and tetrahydrofuran (1 mL) was heatedwithin a microwave for 60 minutes at 140° C. before being cooled to roomtemperature. The mixture was transferred to a mixture of palladium oncarbon (10%, 38 mg) and tetrahydrofuran (1 mL). 1,4-Cyclohexadiene (1mL) was added and the mixture was heated under atmosphere of nitrogenwithin a microwave for 10 minutes at 90° C. before being cooled to roomtemperature. The mixture was filtered and concentrated. The residue wastreated with tetrahydrofuran (10 mL), water (2 mL) and lithium hydroxide(193 mg). The mixture was stirred for 2 h, diluted with ethyl acetate,washed with 2M hydrochloric acid and water. The organic phase was dried(Na₂SO₄) and concentrated. The solid was washed with small amount ofdiethyl ether and treated with dichloromethane (3 mL) thenN,N-dimethylformamide (1 drop) and oxalyl chloride (0.05 mL) were added.The mixture was stirred till solid disappeared and the solution of acidchloride was transferred to a solution of cyclopropylamine (0.3 mL) indichloromethane (5 mL). The resulting mixture was stirred for 30 min.then diluted with ethyl acetate (50 mL). The mixture was washed with 2Mhydrochloric acid and twice with water. The organic phase was dried(Na₂SO₄) and concentrated in vacuo. Purification by preparative HPLC(Gemini column, 0.1% ammonia: acetonitrile eluent) afforded the titlecompound as a solid (70 mg).

MS: APCI(+ve) 362 (M+H⁺).

¹H NMR δ (CDCl₃, 400 MHz) 7.74 (1H, dd), 7.65 (1H, d), 7.44 (3H, m),7.27 (3H, m), 6.85 (1H, d), 6.80 (1H, d), 6.28 (1H, br s), 2.90 (1H, m),2.28 (3H, s), 0.62 (2H, m), 0.88 (2H, m).

Example 117

N-Cyclopropyl-4-methyl-3-[2-oxo-3-(phenylthio)-1(2H)-pyrazinyl]-benzamide

A mixture ofN-cyclopropyl-4-methyl-3-(2-oxo-3-phenoxy-1(2H)-pyrazinyl)-benzamide(Example 116, 55 mg), benzenethiol (0.1 mL) and THF (1 mL) was heatedunder an atmosphere of nitrogen within a microwave for 90 minutes at120° C. Purification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent) afforded the title compound as a solid (32 mg).

MS: APCI(+ve) 378 (M+H⁺).

¹H NMR δ (CDCl₃, 400 MHz) 7.74 (1H, dd), 7.61 (3H, m), 7.47 (3H, m),7.41 (1H, d), 7.15 (1H, d), 6.81 (1H, d), 6.30 (1H, s), 2.88 (1H, m),2.23 (3H, s), 0.86 (2H, m), 0.60 (2H, m).

Example 118

N-Cyclopropyl-4-methyl-3-[2-oxo-3-(phenylthio)-1(2H)-pyrazinyl]-benzamide

A solution of iso-propylmagnesium chloride (2M in tetrahydrofuran, 0.5mL) was added to a stirred mixture ofN-cyclopropyl-4-methyl-3-(2-oxo-3-phenoxy-1(2H)-pyrazinyl)-benzamide(Example 116, 45 mg), benzylthiol (0.2 mL) and tetrahydrofuran (0.5 mL)and the mixture was stirred at room temperature for 36 h. Solid NH₄Cland water were added and the mixture extracted into ethyl acetate. Theorganic phase was dried (Na₂SO₄) and concentrated in vacuo. Purificationby preparative HPLC (Gemini column, 0.1% ammonia: acetonitrile eluent)afforded the title compound as a solid (8 mg).

MS: APCI(+ve) 392 (M+H⁺).

¹H NMR δ (CDCl₃, 300 MHz) 7.72 (1H, d), 7.55 (1H, s), 7.35 (7H, m), 6.81(1H, d), 6.31 (1H, s), 4.34 (2H, m), 2.86 (1H, m), 2.19 (3H, s), 0.83(2H, m), 0.57 (2H, m).

Example 119 and 120

N-Cyclopropyl-4-methyl-3-[3-(4-methyl-2-phenyl-1-piperazinyl)-2-oxo-1(2H)-pyrazinyl]-benzamide(Example 119) and3-[5-bromo-3-(4-methyl-2-phenyl-1-piperazinyl)-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide(Example 120)

A mixture of 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoicacid, methyl ester (Example 1 b, 115 mg), 1-methyl-3-phenyl-piperazine(77 mg), N,N-diisopropylethylamine (0.1 mL) and tetrahydrofuran (1 mL)was heated within a microwave for 30 minutes at 100° C. before beingcooled to room temperature. The mixture was transferred to a mixture ofpalladium on carbon (10%, 50 mg) and tetrahydrofuran (1 mL) and1,4-cyclohexadiene (1 mL) was added. The mixture was heated underatmosphere of nitrogen within a microwave for 2.5 h at 120° C. Anadditional portion of palladium on carbon (50 mg) in tetrahydrofuran (1mL) was added and the mixture was heated for 1 h at 120° C. Aftercooling, cyclopropylamine (0.3 mL) was added followed by dropwiseaddition of a solution of iso-propylmagnesium chloride (2M intetrahydrofuran, 2.5 mL). The mixture was stirred for 10 min. andquenched with sat. aqueous NH₄Cl and extracted into ethyl acetate. Theorganic phase was dried (Na₂SO₄), filtered and concentrated.Purification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent) affordedN-cyclopropyl-4-methyl-3-(4-methyl-3′-oxo-2-phenyl-3,4,5,6-tetrahydro-2H,3′H-[1,2′]bipyrazinyl-4′-yl)-benzamide(49 mg) and3-(6′-Bromo-4-methyl-3′-oxo-2-phenyl-3,4,5,6-tetrahydro-2H,3′H-[1,2]bipyrazinyl-4′-yl)-N-cyclopropyl-4-methyl-benzamide(8 mg).

N-Cyclopropyl-4-methyl-3-[3-(4-methyl-2-phenyl-1-piperazinyl)-2-oxo-1(2H)-pyrazinyl]-benzamide

MS: APCI(+ve) 444 (M+H⁺).

¹H NMR δ (DMSO-d₆, 400 MHz) 8.45 (1H, m), 7.88-7.83 (1H, m), 7.75 and7.71 (1H, 2×d), 7.52-7.42 (3H, m), 7.37-7.28 (2H, m), 7.25-7.16 (1H, m),6.98 (2H, s), 6.17 and 6.07 (1H, 2×br s), 3.27-3.10 (1H, m), 2.90-2.70(2H, m), 2.48-2.37 (2H, m), 2.20 (3H, m), 2.15 (2H, m), 2.11 and 2.04(3H, 2×s), 0.69 (2H, m), 0.55 (2H, m).

3-[5-Bromo-3-[4-methyl-2-phenyl-1-piperazinyl)-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide

MS: APCI(+ve) 522 (M+H⁺).

¹H NMR δ (DMSO-d₆, 400 MHz) 8.42 (1H, m), 7.85 (1H, m), 7.77 and 7.74(1H, 2×d), 7.52-7.41 (3H, m), 7.37-7.28 (2H, m), 7.27-7.19 (2H, m), 6.28and 6.16 (1H, 2×br s), 3.29 (3H, s), 3.18-3.03 (1H, m), 2.89-2.72 (2H,m), 2.48-2.36 (1H, m), 2.20 (3H, m), 2.15 and 2.07 (3H, 2×s), 0.69 (2H,m), 0.55 (2H, m).

Example 121

N-Cyclopropyl-3-[3-[[2-(dimethylamino)ethyl](phenylmethyl)amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

a)3-[3-[[2-(Dimethylamino)ethyl](phenylmethyl)amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoicacid, methyl ester

A mixture of 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoicacid, methyl ester (Example 1 b, 129 mg),N′-benzyl-N,N-dimethylethylenediamine (0.1 mL),N,N-diisopropylethylamnie (0.1 mL) and tetrahydrofuran (1 mL) was heatedwithin a microwave for 15 minutes at 100° C. before being cooled to roomtemperature. The mixture was transferred to a mixture of palladium oncarbon (10%, 50 mg) and tetrahydrofuran (1 mL) and 1,4-cyclohexadiene (1mL) was added. The mixture was heated within a microwave for 60 minutesat 120° C. before being cooled to room temperature. The mixture was isfiltered and the filtrated concentrated in vacuo. Purification bypreparative HPLC (Gemini column, 0.1% ammonia: acetonitrile eluent)afforded the title compound as a solid (50 mg).

¹H NMR δ (CDCl₃, 300 MHz) 8.00 (1H, dd), 7.90 (1H, d), 7.40 (1H, d),7.35-7.17 (5H, m), 6.96 (1H, d), 6.50 (1H, d), 5.16 (1H, d), 4.97 (1H,d), 3.97-3.84 (4H, m), 3.90 (3H, m), 3.71 (1H, m), 2.55 (2H, m), 2.22(6H, s), 2.20 (3H, s).

b)N-Cyclopropyl-3-[3-[[2-(dimethylamino)ethyl](phenylmethyl)amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

A mixture of3-[3-[benzyl-(2-dimethylamino-ethyl)-amino]-2-oxo-2H-pyrazin-1-yl]-4-methyl-benzoicacid, methyl ester (Example 121a, 50 mg), cyclopropylamine (1 mL) andwater (0.5 mL) was stirred at room temperature for 10 days. Purificationby preparative HPLC (Gemini column, 0.1% ammonia: acetonitrile eluent)afforded the title compound as a solid (10 mg).

MS: APCI(+ve) 446 (M+H⁺).

¹H NMR δ (DMSO-d₆, 300 MHz) 8.52 (1H, s), 7.85 (1H, d), 7.74 (1H, s),7.46 (1H, d), 7.38-7.19 (5H, m), 6.93 (1H, m), 6.86 (1H, m), 5.10 (1H,d), 4.84 (1H, d), 3.85 (1H, m), 3.58 (2H, m), 2.85 (1H, m), 2.10 (6H,s), 2.08 (3H, s), 0.69 (2H, m), 0.56 (2H, m).

Example 122

1-[3-[5-Bromo-2-oxo-3-[3-phenyl-4-[2-(1-pyrrolidinyl)ethyl]-1-piperazinyl]-1(2H)-pyrazinyl]-4-methylbenzoyl]-pyrrolidine

A mixture of 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoicacid, methyl ester (Example 1 b, 200 mg), 2-phenylpiperazine (100 mg),N,N-diisopropylethylamine (0.1 mL) and tetrahydrofuran (1 mL) wasstirred at room temperature for 2 h. 1,2-Dibromoethane (0.2 mL) wasadded and the mixture was heated within a microwave for 2 h at 120° C.The mixture was quenched with sat. aqueous NaHCO₃ and extracted withethyl acetate. The organic phase was dried (Na₂SO₄), filtered andconcentrated in vacuo. Pyrrolidine (0.4 mL) was added and the mixturewas heated within a microwave for 15 min. at 100° C. After cooling themixture was purified by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent) to give the title compound (60 mg).

MS: APCI(+ve) 619 (M+H⁺).

¹H NMR δ (DMSO-d₆, 400 MHz) 7.53 (1H, dd), 7.49 and 7.45 (1H, 2×d),7.45-7.27 (6H, m), 7.22 (1H, d), 3.49-3.33 (8H, m), 3.18 (1H, m), 3.09(1H, m), 2.83 (1H, m), 2.48-2.30 (6H, m), 2.24 (4H, m), 2.12 and 2.08(3H, s), 1.83 (4H, m), 1.56 (4H, m), 2.06 (1H, m).

Further elution of the column gave3-[5-bromo-2-oxo-3-[3-phenyl-4-[2-(1-pyrrolidinyl)ethyl]-1-piperazinyl]-1(2H)-pyrazinyl]-4-methyl-benzoicacid, methyl ester (50 mg) that was used in the next step (Example 123).

MS: APCI(+ve) 580 (M+H⁺).

¹H NMR δ (DMSO-d₆, 400 MHz) 7.95 (1H, dd), 7.89 and 7.86 (1H, 2×d), 7.54(1H, t), 7.41-7.26 (5H, m), 7.23 (1H, d), 3.86 and 3.84 (3H, 2×s),3.39-3.27 (1H, m), 3.23-3.02 (2H, m), 2.83 (1H, m), 2.48-2.30 (6H, m),2.24 (4H, m), 2.17 and 2.12 (3H, s), 2.06 (1H, m), 1.57 (4H, m).

Example 123

N-Cyclopropyl-4-methyl-3-[2-oxo-3-[3-phenyl-4-[2-(1-pyrrolidinyl)ethyl]-1-piperazinyl]-1(2H)-pyrazinyl]-benzamide

A mixture of3-[5-bromo-2-oxo-3-[3-phenyl-4-[2-(1-pyrrolidinyl)ethyl]-1-piperazinyl]-1(2H)-pyrazinyl]-4-methyl-benzoicacid, methyl ester (50 mg), ammonium formate (322 mg), palladium 10% oncarbon (22 mg), N,N-diisopropylethylamnie (0.1 mL) and ethanol (2.5 mL)was heated under an atmosphere of nitrogen within a microwave for 30min. at 70° C. The mixture was filtered and concentrated.Cyclopropylamine (0.3 mL) and water (0.5 mL) were added and the mixturewas heated under atmosphere of nitrogen within a microwave for 5 h at100° C. and concentrated in vacuo. Purification by preparative HPLC(Gemini column, 0.1% TFA: acetonitrile eluent) gave the title compound(30 mg).

MS: APCI(+ve) 527 (M+H⁺).

¹H NMR δ (CDCl₃, 300 MHz) 8.04 and 7.88 (1H, d), 7.73 (1H, d), 7.64-7.33(6H, m), 7.02 (1H, m), 6.64 (1H, m), 6.34 (1H, s), 5.06-4.65 (2H, m),3.78 (1H, m), 3.58-2.64 (13H, m), 2.20 and 2.17 (3H, 2×s), 2.00 (4H, m),0.86 (2H, m), 0.60 (2H, m).

Example 124

3-[3-[[[3-(Aminomethyl)phenyl]methyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide

A mixture of[[3-[[[4-[5-[(cyclopropylamino)carbonyl]-2-methylphenyl]-3,4-dihydro-3-oxopyrazinyl]amino]methyl]phenyl]methyl]-carbamicacid, 1,1-dimethylethyl ester (Example 51, 90 mg), dichloromethane (2mL) and trifluoroacetic acid (0.5 mL) was stirred at room temperaturefor 30 min. The mixture was concentrated in vacuo. Purification bypreparative HPLC (Gemini column, 0.1% ammonia: acetonitrile eluent)afforded the title compound as a solid (22 mg).

MS: APCI(+ve) 404 (M+H⁺)

¹H NMR δ (DMSO-d₆, 400 MHz) 8.43 (1H, d), 7.86 (2H, m), 7.75 (1H, s),7.49 (1H, d), 7.29 (1H, s), 7.27-7.13 (3H, m), 6.83 (1H, d), 6.70 (1H,d), 4.58 (1H, dd), 4.47 (1H, dd), is 3.69 (2H, s), 3.29 (2H, s), 2.84(1H, m), 2.11 (3H, s), 0.68 (2H, m), 0.55 (2H, m).

Example 125

3-[3-[[[4-(Aminomethyl)phenyl]methyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide

The title compound was prepared from Example 54 using the methoddescribed for Example 124.

MS: APCI(+ve) 404 (M+H+).

¹H NMR δ (DMSO-d₅, 400 MHz) 8.43 (1H, d), 7.87 (2H, m), 7.75 (1H, s),7.49 (1H, d), 7.26 (4H, s), 6.82 (1H, d), 6.69 (1H, d), 4.55 (1H, dd),4.45 (1H, dd), 3.67 (2H, s), 2.84 (1H, m), 2.11 (3H, s), 0.69 (2H, m),0.54 (2H, m).

Example 126 and Example 127

N-Methoxy-4-methyl-3-[2-oxo-3-(3-phenyl-1-piperazinyl)-1(2H)-pyrazinyl]-benzamide(Example 126) and3-(3-cyclopentyl-2-oxo-1(2H)-pyrazinyl)-N-methoxy-4-methyl-benzamide(Example 127)

A mixture of 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoicacid, methyl ester (Example 1 b, 0.21 g), N,N-diisopropylethylamnie (0.2mL), 2-phenylpiperazine (0.12 g) and tetrahydrofuran (1 mL) was stirredat room temperature for 2 h. Ethanol (3 mL) was added followed by wet10% palladium on carbon (50 mg) and ammonium formate (0.45 g). Themixture was stirred under nitrogen atmosphere at 70° C. for 30 min. Themixture was filtered through a pad of Celite. The filtrate concentratedin vacuo. The residue was treated with O-methylhydroxylaminehydrochloride (180 mg) and tetrahydrofuran (1 mL) followed by additionof cyclopentylmagnesium bromide (2M in diethyl ether, 0.8 mL). Themixture was stirred for 10 min., quenched with sat. NH₄Cl and extractedinto ethyl acetate. The organic phase was concentrated in vacuo.Purification by preparative HPLC (Gemini column, 0.1% TFA: acetonitrileeluent) affordedN-methoxy-4-methyl-3-[2-oxo-3-(3-phenyl-1-piperazinyl)-1(2H)-pyrazinyl]-benzamidetrifluoroacetate (50 mg) and3-(3-cyclopentyl-2-oxo-2H-pyrazin-1-yl)-N-methoxy-4-methyl-benzamidetrifluoroacetate (67 mg).

N-Methoxy-4-methyl-3-[2-oxo-3-(3-phenyl-1-piperazinyl)-1(2H)-pyrazinyl]-benzamide,trifluoroacetate

MS: APCI(+ve) 420 (M-±1±).

¹H NMR δ (DMSO-d₆, 400 MHz) 11.81 (1H, s), 7.77 (1H, dd), 7.66 and 7.63(1H, 2×d), 7.54-7.46 (3H, m), 7.45-7.32 (3H, m), 7.08-7.03 (2H, m),4.83-4.62 (2H, m), 4.24 (1H, s), 3.71 and 3.70 (3H, 2×s), 3.21-2.99 (4H,m), 2.13 and 2.10 (3H, 2×s).

3-(3-Cyclopentyl-2-oxo-2H-pyrazin-1-yl)-N-methoxy-4-methyl-benzamide,trifluoroacetate

MS: APCI(+ve) 328 (M+H⁺).

¹H NMR δ (DMSO-d₅, 400 MHz) 11.80 (1H, s), 7.79 (1H, dd), 7.67 (1H, d),7.52 (1H, d), 7.44 (1H, d), 7.32 (1H, d), 3.88 (1H, s), 3.70 (3H, s),3.49 (1H, quintet), 2.09 (3H, s), 2.00-1.86 (2H, m), 1.84-1.54 (6H, m).

Example 128

N-Cyclopropyl-4-methyl-3-[3-[[[2-(methylthio)phenyl]methyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

a) 4-Methyl-3-(2-oxo-3-phenoxy-1(2H)-pyrazinyl)-benzoic acid, methylester

A mixture of 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoicacid, methyl ester (Example 1 b, 400 mg), phenol (400 mg),N,N-diisopropylethylamine (0.4 mL) and tetrahydrofuran (2 mL) was heatedwithin a microwave for 3 h at 120° C. before being cooled to roomtemperature. The mixture was transferred to a mixture of palladium oncarbon (10%, 38 mg) and tetrahydrofuran (1 mL). 1,4-Cyclohexadiene (2mL) was added and the mixture was heated under atmosphere of nitrogenwithin a microwave for 15 minutes at 90° C. before being cooled to roomtemperature. The mixture was filtered and concentrated to give a crudeproduct that was used in the next step without purification.

b)N-Cyclopropyl-4-methyl-3-[3-[[[2-(methylthio)phenyl]methyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

A mixture of 4-methyl-3-(2-oxo-3-phenoxy-2H-pyrazin-1-yl)-benzoic acid,methyl ester (Example 128a, 111 mg), 2-(methylthio)-benzenemethanamine(100 mg) and tetrahydrofuran (1 mL) was heated within a microwave for 5h at 120° C. before being cooled to room temperature. Cyclopropylamine(0.2 mL) was added followed by addition of cyclopentylmagnesium bromide(2M in diethyl ether, 0.8 mL). The mixture was stirred for 10 min.,quenched with sat. NH₄Cl and extracted into ethyl acetate. The organicphase was concentrated in vacuo. Purification by preparative HPLC(Gemini column, 0.1% ammonia: acetonitrile eluent) afforded the titlecompound as a solid (39 mg).

MS: APCI(+ve) 421 (M+H)⁺.

¹H NMR δ (DMSO-d₆, 300 MHz) 8.45 (1H, d), 7.88 (1H, dd), 7.80-7.73 (2H,m), 7.50 (1H, d), 7.33-7.22 (2H, m), 7.19-7.08 (2H, m), 6.81 (1H, d),6.72 (1H, d), 4.57 (1H, dd), 4.46 (1H, dd), 2.91-2.80 (1H, m), 2.51 (3H,s), 2.13 (3H, s), 0.70 (2H, m), 0.57 (2H, m).

Example 129

3-[3-[[(2-Chlorophenyl)methyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide

The title compound was prepared from of4-methyl-3-(2-oxo-3-phenoxy-1(2H)-pyrazinyl)-benzoic acid, methyl ester(Example 128a) and 2-chlorobenzenemethanamine using the method describedfor Example 128.

MS: APCI(+ve) 409 (M+H⁺).

¹H NMR δ (DMSO-d₆, 400 MHz) 8.45 (1H, d), 7.92 (1H, t), 7.88 (1H, dd),7.78 (1H, d), 7.50 (1H, d), 7.45 (1H, m), 7.34-7.24 (3H, m), 6.81 (1H,d), 6.74 (1H, d), 4.65 (1H, dd), 4.55 (1H, dd), 2.86 (1H, m), 2.14 (3H,s), 0.70 (2H, m), 0.56 (2H, m).

Example 130

3-[3-[[(3-Chlorophenyl)methyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide

The title compound was prepared from4-methyl-3-(2-oxo-3-phenoxy-1(2H)-pyrazinyl)-benzoic acid, methyl ester(Example 128a) and 3-chlorobenzenemethanamine using the method describedfor Example 128.

MS: APCI(+ve) 409 (M+H⁺).

¹H NMR δ (DMSO-d₆, 400 MHz) 8.43 (1H, d), 8.03 (1H, t), 7.87 (1H, dd),7.76 (1H, d), 7.49 (1H, d), 7.39-7.36 (1H, m), 7.34 (1H, d), 7.32-7.26(2H, m), 6.82 (1H, d), 6.72 (1H, d), 4.58 (1H, dd), 4.48 (1H, dd), 2.85(1H, m), 2.11 (3H, s), 0.69 (2H, m), 0.55 (2H, m).

Example 131

N-Cyclopropyl-4-methyl-3-[3-[[(1R)-3-(4-methyl-1-piperazinyl)-3-oxo-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

A solution of iso-propylmagnesium chloride (2M in tetrahydrofuran, 1.3mL) was added to a stirred mixture of(R)-[[4-[5-[(cyclopropylamino)carbonyl]-2-methylphenyl]-3,4-dihydro-3-oxopyrazinyl]amino]-benzenepropanoicacid, 1,1-dimethylethyl ester (Example 87, 100 mg), 1-methylpiperazine(0.2 mL) and tetrahydrofuran (2 mL). The reaction mixture was heatedwithin a microwave for 20 min. at 60° C. before being cooled to roomtemperature and quenched with sat. aqueous NH₄Cl. The mixture wasextracted into ethyl acetate. The organic phase was concentrated invacuo. Purification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent) afforded the title compound as a solid (60 mg).

MS: APCI(+ve) 415 (M+H⁺).

¹H NMR δ (DMSO-d₆, 400 MHz) 8.44 and 8.39 (1H, 2×d), 7.91-7.83 (2H, m),7.74 and 7.72 (1H, 2×d), 7.49 and 7.48 (1H, 2×d), 7.43-7.36 (2H, m),7.31 and 7.30 (2H, 2×t), 7.25-7.18 (1H, m), 6.797 and 6.794 (1H, 2×d),6.683 and 6.679 (1H, 2×d), 5.47 (1H, m), 3.45-3.30 (8H, m), 3.19 (1H,dd), 2.88-2.80 (1H, m), 2.76 (1H, dd), 2.13, 2.11, 2.10, 2.08 (6H, 4×s),0.68 (2H, m), 0.55 (2H, m).

Example 132

N-Methoxy-4-methyl-3-[2-oxo-3-(1-pyrrolidinyl)-1(2H)-pyrazinyl]-benzamide

The title compound was prepared from3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methylester using the method described in Example 126.

MS: APCI(+ve) 329 (M+H⁺).

¹H NMR δ (DMSO-d₆, 400 MHz) 11.81 (1H, s), 7.76 (1H, d), 7.64 (1H, s),7.50 (1H, d), 6.84 (1H, d), 6.78 (1H, d), 3.91-3.72 (4H, m), 3.70 (3H,s), 2.15 (3H, s), 1.96-1.82 (4H, m).

Example 133

N-Cyclopropyl-4-methyl-3-[2-oxo-3-[[2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]ethyl]amino]-1(2H)-pyrazinyl]-benzamide

To a stirred solution of3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methylester (Example 1 b, 0.1 g) in tetrahydrofuran (2 mL) was addedtriethylamine (0.17 mL) and 4-(2-aminoethyl)-phenol (34 mg). Thereaction mixture was stirred for 12 h and 1-(2-chloroethyl)-pyrrolidinehydrochloride (120 mg), cesium carbonate (646 mg) andN,N-dimethylformamide (2 mL) were added. The mixture was heated within amicrowave at 130° C. for 100 minutes. The reaction mixture was cooled toroom temperature and quenched with sat. NaHCO₃. The mixture wasextracted with dichloromethane. The pooled organics were washed withwater and brine, dried (Na₂SO₄), filtered and the solvent removed. Theproduct was taken up in tetrahydrofuran (3 mL) followed by the additionof cyclopropylamine (0.15 mL) and cyclopentylmagnesium bromide (2M indiethyl ether, 0.75 mL) portionwise. The reaction mixture was stirredunder nitrogen for 1 h before the addition of ethanol (2 mL), ammoniumformate (300 mg) and 10% palladium on carbon (30 mg). The reactionmixture was heated within a microwave at 100° C. for 60 minutes,filtered and washed with ethanol. The filtrate was concentrated invacuo. Purification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent) afforded the title compound (60 mg).

MS: APCI(+ve) 502 (M+H±).

¹H NMR δ (DMSO-d₅, 400 MHz) 8.43 (1H, d), 7.86 (1H, dd), 7.73 (1H, d),7.48 (1H, d), 7.29 (1H, t), 7.17-7.12 (2H, m), 6.89-6.84 (3H, m), 6.68(1H, d), 4.02 (2H, t), 3.60-3.44 (2H, m), 2.88-2.78 (3H, m), 2.76 (2H,t), 2.54-2.46 (4H, m), 2.09 (3H, s), 1.71-1.65 (4H, m), 0.71-0.66 (2H,m), 0.58-0.53 (2H, m).

Example 134

N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(1-pyrrolidnyl)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

a) α,α-Dimethyl-2-(phenylmethoxy)-benzenemethanamine

A suspension of anhydrous cerium chloride (1.0 g) in anhydroustetrahydrofuran (10 mL) under nitrogen was stirred for 30 minutes andthen cooled to −78° C. A solution of methyl lithium in diethyl ether(1.6M, 3 mL) was added and the reaction mixture was stirred for 30minutes. A solution of 2-(phenylmethoxy)-benzonitrile (0.3 g) intetrahydrofuran (2 mL) was added. The reaction was stirred and graduallywarmed to −10° C. then cooled to −78° C. and quenched with conc. ammoniasolution. The mixture was stirred for 12 h then filtered and the solidwashed with ethyl acetate. The organic phase was separated and theaqueous phase being extracted twice with ethyl acetate. The pooledorganics were washed with water, brine then dried (Na₂SO₄), filtered andconcentrated in vacuo. Purification using SCX chromatography affordedthe subtitle compound (360 mg).

b)N-Cyclopropyl-3-[3-[[1-(2-hydroxyphenyl)-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

To a stirred solution of3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid methyl ester(Example 1b, 0.4 g) in tetrahydrofuran (3 mL) within a microwave vialwas added N,N-diisopropylethylamine (200 μL) andα,α-dimethyl-2-(phenylmethoxy)-benzenemethanamine (360 mg). The reactionwas heated in a microwave for 100 minutes at 120° C. The reactionmixture was cooled to room temperature and cyclopropylamine (0.5 mL) wasadded. A solution of cyclopentylmagnesium bromide (2M in diethyl ether,3 mL) was added dropwise. The reaction mixture was stirred for 30minutes. Ethanol (2 mL) and sat. aqueous NH₄Cl were added and themixture extracted with ethyl acetate. The pooled organic were washedwith brine, dried (Na₂SO₄), filtered and concentrated in vacuo. Theresidue was taken up in ethanol (3 mL) and ammonium formate (0.3 g) and10% palladium on carbon (40 mg) were added. The reaction mixture washeated within a microwave for 30 minutes at 100° C. and then 90 minutesat 60° C. before being cooled to room temperature, then filtered andwashed with ethanol. The filtrate was concentrated in vacuo. The residuewas purified (SiO₂ chromatography eluting with iso-hexane: ethylacetate) to afford the subtitle compound as a solid (330 mg).

MS: APCI(+ve) 419 (M+H⁺).

¹H NMR δ (DMSO-d₆, 400 MHz) 9.50 (1H, s), 8.43 (1H, d), 7.86 (1H, dd),7.73 (1H, d), 7.48 (1H, d), 7.24 (1H, dd), 7.06-7.01 (1H, m), 6.99-6.97(1H, m), 6.79-6.72 (2H, m), 6.70 (1H, d), 6.64 (1H, d), 2.89-2.81 (1H,m), 2.10 (3H, s), 1.85 (3H, s), 1.82 (3H, s), 0.71-0.66 (2H, m),0.57-0.53 (2H, m).

Example 135

N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(1-pyrrolidinyl)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

To a stirred solution ofN-cyclopropyl-3-(3-(2-(2-hydroxyphenyl)propan-2-ylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzamide(Example 134, 0.1 g) in N,N-dimethylformamide (3 mL),N-(2-chloroethyl)-pyrrolidine, hydrochloride (0.12 g) and cesiumcarbonate (0.47 g) were added. The reaction was stirred under nitrogenat 80° C. for 12 h. After 2 h additional batches ofN-(2-chloroethyl)-pyrrolidine hydrochloride (0.12 g) and cesiumcarbonate (0.47 g) were added. The reaction mixture was stirred at 100°C. for 10 h and then at 90° C. for 10 h. Ethyl acetate was added and themixture was washed with water and brine. The organic phase was dried(Na₂SO₄), filtered and concentrated in vacuo. Purification bypreparative HPLC (Gemini column —acetonitrile/0.1% ammonia mobile phase)afforded the title compound as a solid (34 mg).

MS: APCI(+ve) 516 (M+H⁺).

¹H NMR δ (DMSO-d₆, 400 MHz) 8.42 (1H, d), 7.86 (1H, dd), 7.72 (1H, d),7.48 (1H, d), 7.32 (1H, dd), 7.21-7.16 (1H, m), 6.98 (1H, d), 6.92-6.86(2H, m), 6.65 (1H, d), 6.62 (1H, d), 4.06-3.94 (2H, m), 2.88-2.80 (1H,m), 2.79 (2H, t), 2.52-2.43 (4H, m), 2.09 (3H, s), 1.83 (6H, s),1.69-1.61 (4H, m), 0.72-0.66 (2H, m), 0.57-0.51 (2H, m).

Example 136

N-Cyclopropyl-3-[3-[[(1R,2R)-3-hydroxy-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

a) (2S)-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-N-methoxy-N,2-dimethyl-propanamide

A solution of iso-propylmagnesium chloride (2M in tetrahydrofuran, 28mL) was added dropwise to a stirred mixture of(2S)-3-(tert-butyl-diphenyl-silanyloxy)-2-methyl-propionic acid, methylester (Eur. J. Org. Chem. 2006, 3645, 7.5 g), O,N-dimethylhydroxylaminehydrochloride (2.55 g) and tetrahydrofuran (65 mL) at 0° C. Aftercompletion the mixture was quenched with sat. aqueous NH₄Cl andextracted into ethyl acetate. The organic phase was dried (Na₂SO₄),filtered and concentrated in vacuo to give the crude product as a solid(8.1 g).

¹H NMR δ (CDCl₃, 400 MHz) 7.72-7.62 (4H, m), 7.45-7.34 (6H, m), 3.93(1H, dd), 3.66 (3H, s), 3.59 (1H, dd), 3.20 (3H, s), 3.26-3.14 (1H, m),1.08 (3H, d), 1.03 (9H, s)

b)(R)—N-[(1R,2R)-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-2-methyl-1-phenylpropyl]-2-methyl-2-propanesulfinamide

A solution of diisobutylaluminium hydride in tetrahydrofuran (1M, 50 mL)was added dropwise to a stirred solution of(2S)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-N-methoxy-N,2-dimethyl-propanamide(Example 136a, 6.2 g) in tetrahydrofuran (40 mL) at 0° C. The mixturewas stirred for 30 minutes and poured onto a mixture of ethyl acetate(250 mL) and 2M hydrochloric acid (100 mL). The organic phase was washedwith brine, dried (Na₂SO₄), filtered and concentrated in vacuo to givethe crude aldehyde. Tetrahydrofuran (30 mL) was added followed by(R)-(+)-2-methyl-2-propanesulfinamide (2.6 g) and titanium ethoxide (10mL). The mixture was stirred at room temperature for 90 min., thendiluted with ethyl acetate (300 mL) and quenched with brine (100 mL).The mixture was stirred for 1 h. The organic phase was separated, dried(Na₂SO₄), filtered through a pad of Celite and concentrated in vacuo togive the crude sulfinimine, which was dissolved in dry dichloromethane(90 mL) and the solution was cooled to 50° C. A solution ofphenylmagnesium bromide in diethyl ether (3M, 13 mL) was added dropwiseand the reaction mixture was warmed up to 0° C. over 3 h, quenched withsat. aqueous NH₄Cl (150 mL) and extracted into dichloromethane. Theorganic phase was dried (Na₂SO₄), filtered and concentrated in vacuo.The residue was purified (SiO₂ chromatography eluting with iso-hexane:ethyl acetate (0-100%)) to give the subtitle compound (5.2 g).

¹H NMR δ (CDCl₃, 400 MHz) 7.66-7.62 (3H, m), 7.59-7.55 (3H, m),7.45-7.22 (14H, m), 4.59 (1H, dd), 3.87 (1H, d), 3.55 (1H, dd), 3.40(1H, dd), 2.23 (1H, m), 1.16 (9H, s), 1.06 (9H, s), 0.88 (3H, d).

c)3-[3-[[(1R,2R)-3-Hydroxy-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoicacid, methyl ester

A mixture of(R)—N-[(1R,2R)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2-methyl-1-phenylpropyl]-2-methyl-2-propanesulfinamide(Example 136b, 5.2 g), methanol (25 mL) and a solution of hydrogenchloride in 1,4-dioxane (4M, 25 mL) was stirred at 50° C. for 7 h andleft at room temperature for 70 h. The mixture was concentrated in vacuoand the residue was washed with ether to give the crude aminehydrochloride (2.0 g).3-(3,5-Dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methylester (Example 1b, 3.5 g) was added followed byN,N-diisopropylethylamine (4 mL) and tetrahydrofuran (50 mL). Themixture was stirred at 50° C. for 24 h. After cooling to roomtemperature, the mixture was diluted with ethyl acetate (200 mL) andwashed with sat. aqueous NaHCO₃. The organic phase was dried (Na₂SO₄),filtered and concentrated in vacuo. Ethanol (50 mL) was added undernitrogen atmosphere followed by wet palladium on carbon (10%, 227 mg),ammonium formate (3 g) and N,N-diisopropylethylamine (2 mL). The mixturewas stirred at 70° C. for 2 h, cooled to room temperature, filteredthrough a pad of Celite and concentrated in vacuo. The residue wasdiluted with ethyl acetate (200 mL) and washed with water. The organicphase was dried (Na₂SO₄), filtered and concentrated in vacuo to give thesubtitle compound (3.5g).

¹H NMR δ (DMSO-d₆, 400 MHz) 7.96 (1H, d), 7.91 and 7.88 (1H, 2×d), 7.84and 7.79 (1H, 2×d), 7.58 and 7.56 (1H, 2×d), 7.43-7.36 (2H, m), 7.31(2H, t), 7.25-7.19 (1H, m), 6.76 and 6.755 (1H, 2×d), 6.662 and 6.657(1H, 2×d), 5.02 (1H, dd), 4.77 (1H, d), 3.86 and 3.84 (3H, 2×s),3.22-3.14 (2H, m), 2.29-2.13 (1H, m), 2.16 and 2.09 (3H, 2×s), 0.87 (3H,d).

d)N-Cyclopropyl-3-[3-[[(1R,2R)-3-hydroxy-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

A solution of iso-propylmagnesium chloride (2M in tetrahydrofuran, 5.5mL) was added dropwise to a stirred mixture of3-[3-[[(1R,2R)-3-hydroxy-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoicacid, methyl ester (Example 136c, 500 mg), cyclopropylamine (0.3 mL) andtetrahydrofuran (20 mL) at 0° C. After 15 min the reaction was quenchedwith sat. aqueous NH₄Cl and extracted into ethyl acetate. The organicphase was dried (Na₂SO₄), filtered and concentrated in vacuo to give acrude title product (525 mg). Purification by preparative HPLC (Geminicolumn, 0.1% ammonia: acetonitrile eluent) afforded the title compound.

MS: APCI(+ve) 433 (M+H⁺).

¹H NMR δ (DMSO-d₆, 400 MHz) 8.45 and 8.38 (1H, 2×d), 7.97-7.83 (2H, m),7.75 and 7.70 (1H, 2×d), 7.49 and 7.47 (2H, 2×d), 7.44-7.20 (5H, m),6.77 and 6.76 (1H, 2×d), 6.65 and 6.64 (1H, 2×d), 5.05-4.99 (1H, m),4.80 and 4.74 (1H, 2×t), 3.23-3.12 (2H, m), 2.90-2.79 (1H, m), 2.30-2.13(1H, m), 2.12 and 2.05 (3H, 2×s), 0.87 (3H, d), 0.72-0.63 (2H, m),0.60-0.50 (2H, m).

Example 137

N-Cyclopropyl-3-[3-[[(1R,2R)-3-hydroxy-2-methyl-1-(1-naphthalenyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

a)3-[3-[[(1R,2R)-3-Hydroxy-2-methyl-1-(1-naphthalenyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoicacid, methyl ester

The title compound was prepared from(2S)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-N-methoxy-N,2-dimethyl-propanamide(Example 136a) and 1-naphthalenylmagnesium bromide using methodsdescribed in the Example 136a and 136b.

¹H NMR δ (DMSO-d₆, 400 MHz) 8.34 and 8.33 (1H, 2×d), 8.05 (1H, d), 7.98and 7.84 (1H, 2×d), 7.88 (1H, d), 7.80 (1H, t), 7.61 (1H, t), 7.56-7.37(4H, m), 7.16 (1H, d), 6.90 (1H, d), 6.54-6.46 (1H, m), 6.45 and 6.44(1H, 2×d), 3.93 and 3.88 (3H, 2×s), 3.71-3.63 (1H, m), 3.49-3.40 (1H,m), 2.55-2.38 (1H, m), 2.31 and 2.17 (3H, 2×s), 0.76 and 0.75 (3H, 2×d).

b)N-Cyclopropyl-3-[3-[[(1R,2R)-3-hydroxy-2-methyl-1-(1-naphthalenyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

The title compound was prepared from3-[3-((1R,2R)-3-hydroxy-2-methyl-1-naphthalen-1-yl-propylamino)-2-oxo-2H-pyrazin-1-yl]-4-methyl-benzoicacid, methyl ester (Example 137a) using the method described in theExample 136c.

MS: APCI(+ve) 483 (M+H⁺).

¹H NMR δ (DMSO-d₆, 400 MHz) 8.47-8.36 (2H, m), 7.95 (1H, d), 7.87 (1H,d), 7.82 (1H, d), 7.77 and 7.71 (1H, 2×d), 7.65-7.45 (6H, m), 6.73 and6.72 (1H, 2×d), 6.67 and 6.67 (1H, 2×d), 6.08 (1H, dd), 4.87 and 4.83(1H, 2×t), 3.35-3.26 (2H, m), 2.90-2.78 (1H, m), 2.41-2.30 (1H, m), 2.15and 2.06 (3H, 2×s), 0.87 (3H, d), 0.73-0.63 (2H, m), 0.60-0.50 (2H, m).

Example 138

N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-(4-morpholinyl)-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

a)N-Cyclopropyl-4-methyl-3-[3-[[(1R,2R)-2-methyl-3-oxo-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

A solution of Dess-Martin periodinane (600 mg) in dichloromethane (3 mL)was added dropwise to a solution ofN-cyclopropyl-3-(3-((1R,2R)-3-hydroxy-2-methyl-1-phenylpropylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzamide(Example 136, 405 mg) in dichloromethane (4 mL) at 25° C. The resultingmixture was stirred at 25° C. for 30 minutes. The reaction mixture wasquenched with sat. aqueous Na₂S₂O₃ (7 mL) and sat. aqueous NaHCO₃. Themixture was stirred for 15 min. and extracted into dichloromethane. Theorganic phase was dried (Na₂SO₄), filtered and evaporated to affordcrude product (475 mg) that was used in the next step withoutpurification.

b)N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-(4-morpholinyl)-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

To a solution ofN-cyclopropyl-4-methyl-3-[3-((1R,2R)-2-methyl-3-oxo-1-phenylpropylamino)-2-oxo-2H-pyrazin-1-yl]-benzamide(Example 138a, 135 mg) in dichloromethane (4 mL) morpholine (0.2 mL) wasadded followed by sodium triacetoxyborohydride (70 mg). The reaction wasstirred at room temperature for 17 h and quenched with sat. aqueousNaHCO₃. The mixture was stirred for 15 min. and extracted intodichloromethane. The organic phase was concentrated in vacuo.Purification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent) afforded the title compound (45 mg).

MS: APCI(+ve) 502 (M+H⁺).

¹H NMR δ (DMSO-d₆, 400 MHz) 9.23 and 9.08 (1H, 2×d), 8.45 and 8.41 (1H,2×d), 7.87 (1H, dd), 7.74 and 7.70 (1H, 2×d), 7.49 and 7.48 (1H, 2×d),7.38-7.21 (5H, m), 6.732 and 6.73 (1H, 2×d), 6.64 (1H, d), 5.07 (1H,dd), 3.79-3.58 (4H, m), 2.89-2.79 (1H, m), 2.37-2.21 (3H, m), 2.14 (1H,m), 2.11 and 2.06 (3H, 2×s), 2.02-1.94 (2H, m), 0.79 and 0.78 (3H, 2×d),0.73-0.63 (2H, m), 0.59-0.51 (2H, m).

The following Examples 139-157 (Table 3) were prepared from thecorresponding alcohols and amines using the general procedure describedfor Example 138b (in some reactions a mixture of diasteroisomers wasobtained. Isomers were separated by preparative HPLC).

Example 139

N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-(4-methyl-1-piperazinyl)-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 140

3-[3-[[(1R,2S)-3-(4-Acetyl-1-piperazinyl)-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide

Example 141

N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-1-phenyl-3-(1-piperidinyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 142

N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-1-phenyl-3-(1-pyrrolidinyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 143

N-Cyclopropyl-3-[3-[[(1R,2S)-3-(dimethylamino)-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 144

N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-1-(1-naphthalenyl)-3-(1-pyrrolidinyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 145

N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-(4-morpholinyl)-1-(1-naphthalenyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 146

N-cyclopropyl-3-[3-[[(1R,2S)-3-(diethylamino)-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 147

N-Cyclopropyl-3-[3-[[(1R,2S)-3-[(2R)-2-(methoxymethyl)-1-pyrrolidinyl]-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 148

N-Cyclopropyl-3-[3-[[(1R,2R)-3-[(2R)-2-(methoxymethyl)-1-pyrrolidinyl]-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 149

N-Cyclopropyl-3-[3-[[(1R,2S)-3-[(2S)-2-(methoxymethyl)-1-pyrrolidinyl]-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 150

N-Cyclopropyl-3-[3-[[(1R,2R)-3-[(2S)-2-(methoxymethyl)-1-pyrrolidinyl]-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 151

N-Cyclopropyl-3-[3-[[(1R,2S)-3-[4-(hydroxymethyl)-1-piperidinyl]-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 152

N-Cyclopropyl-3-[3-[[(1R,2S)-3-(4-hydroxy-1-piperidinyl)-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 153

N-Cyclopropyl-3-[3-[[(1R,2S)-3-[(1,1-dimethylethyl)amino]-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 154

N-Cyclopropyl-3-[3-[[(1R,2S)-3-[(1,1-dimethylethyl)methylamino]-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 155

N-Cyclopropyl-3-[3-[[(1R,2S)-3-[[2-(dimethylamino)ethyl]amino]-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 156

N-Cyclopropyl-3-[3-[[(1R,2S)-3-[[2-(dimethylamino)ethyl]methylamino]-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 157

N-Cyclopropyl-3-[3-[[(1R,2S)-3-[(2,2-dimethylpropyl)amino]-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

TABLE 3

MS [M + H]⁺ Example R m/z ¹H NMR δ (DMSO-d₆) 139

515 8.78 and 8.69 (1H, 2 × d), 8.45 and 8.40 (1H, 2 × d), 7.86 (1H, dd),7.74 and 7.70 (1H, 2 × d), 7.48 and 7.47 (1H, 2 × d), 7.38- 7.29 (5H,m), 7.27-7.21 (2H, m), 6.75 and 6.74 (1H, 2 × d), 6.641 and 6.635 (1H, 2× d), 5.03 (1H, m), 2.90-2.79 (1H, m), 2.46-2.29 (2H, m), 2.20-2.13 (8H,m), 2.11-2.06 (2H, m), 2.11 and 2.05 (3H, 2 × s), 1.93-1.83 (1H, m),0.80 (3H, d), 0.73- 0.63 (2H, m), 0.60-0.50 (2H, m) 140

543 9.32 and 9.17 (1H, 2 × d), 8.45 and 8.40 (1H, 2 × d), 7.86 (1H, dd),7.74 and 7.70 (1H, 2 × d), 7.49 and 7.47 (1H, 2 × d), 7.38- 7.21 (5H,m), 6.735 and 6.73 (1H, 2 × d), 6.64 (1H, d), 5.08 (1H, dd), 3.67-3.43(5H, m), 2.90-2.78 (1H, m), 2.37-2.13 (5H, m), 2.11 and 2.05 (3H, 2 ×s), 2.01- 1.94 (1H, m), 1.96 and 1.955 (3H, 2 × s), 0.79 and 0.78 (3H, 2× d), 0.72-0.64 (2H, m), 0.59-0.51 (2H, m) 141

500 9.32 and 9.21 (1H, 2 × d), 8.45 and 8.41 (1H, 2 × d), 7.87 (1H, dd),7.74 and 7.71 (1H, 2 × d), 7.49 and 7.48 (1H, 2 × d), 7.38- 7.20 (5H,m), 6.71 (1H, d), 6.62 (1H, d), 5.06 (1H, dd), 2.89-2.80 (1H, m), 2.58-2.41 (1H, m), 2.30-2.16 (2H, m), 2.16- 2.02 (1H, m), 2.11 and 2.05 (3H,2 × s), 1.95-1.86 (1H, m), 1.75-1.63 (2H, m), 1.64-1.51 (2H, m),1.44-1.31 (2H, m), 0.77 and 0.76 (3H, 2 × d), 0.73-0.64 (2H, m),0.60-0.51 (2H, m) 142

486 9.17 and 9.00 (1H, 2 × d), 8.45 and 8.40 (1H, 2 × d), 7.86 (1H, d),7.74 and 7.69 (1H, 2 × d), 7.48 and 7.47 (1H, 2 × d), 7.38- 7.28 (4H,m), 7.28-7.21 (1H, m), 6.73 and 6.72 (1H, 2 × d), 6.62 (1H, d), 5.10-5.02 (1H, m), 2.89-2.79 (2H, m), 2.61- 2.30 (4H, m), 2.11 and 2.04 (3H,2 × s), 2.05-1.99 (1H, m), 1.82-1.64 (4H, m), 0.83-0.76 (3H, m),0.73-0.63 (3H, m), 0.60-0.50 (2H, m) 143

460 8.80 and 8.62 (1H, 2 × d), 8.45 and 8.40 (1H, 2 × d), 7.86 (1H, d),7.74 and 7.70 (1H, 2 × d), 7.49 and 7.48 (1H, 2 × d), 7.37- 7.20 (5H,m), 6.735 and 6.73 (1H, 2 × d), 6.63 (1H, d), 5.10-5.03 (1H, m), 2.89-2.80 (1H, m), 2.49-2.32 (2H, m), 2.15- 2.04 (9H, m), 1.97-1.90 (1H, m),0.81 and 0.79 (3H, 2 × d), 0.72-0.64 (2H, m), 0.59- 0.51 (2H, m) 144

536 8.49 and 8.26 (1H, 2 × d), 8.46 and 8.41 (1H, 2 × d), 8.39 (1H, d),7.94 (1H, dt), 7.86 (1H, d), 7.77 and 7.69 (1H, 2 × d), 7.63-7.45 (5H,m), 6.71 and 6.69 (1H, 2 × d), 6.64 and 6.63 (1H, 2 × d), 6.12 (1H, m),2.59-2.38 (6H, m), 2.23-2.15 (1H, m), 2.13 and 2.04 (3H, 2 × s),1.82-1.68 (4H, m), 0.82 and 0.80 (3H, 2 × d), 0.73-0.63 (2H, m),0.60-0.50 (2H, m) 145

552 8.49-8.18 (3H, m), 7.95 and 7.87 (1H, 2 × d), 7.83 (1H, d), 7.77 and7.70 (1H, 2 × d), 7.63-7.45 (5H, m), 6.71 and 6.70 (1H, 2 × d), 6.65 and6.64 (1H, 2 × d), 6.21-6.11 (1H, m), 3.77-3.58 (5H, m), 2.91-2.78 (1H,m), 2.41-2.24 (5H, m), 2.16-2.07 (1H, m), 2.13 and 2.05 (3H, 2 × s),0.80 and 0.78 (3H, 2 × d), 0.73-0.63 (2H, m), 0.59-0.50 (2H, m) 146

488 8.69 and 8.63 (1H, 2 × d), 8.45 and 8.41 (1H, 2 × d), 7.86 (1H, dd),7.73 and 7.72 (1H, 2 × d), 7.49 and 7.48 (1H, 2 × d), 7.36- 7.28 (4H,m), 7.27-7.19 (1H, m), 6.732 and 6.727 (1H, 2 × d), 6.64 (1H, d), 5.11-5.01 (1H, m), 2.90-2.79 (1H, m), 2.64- 2.30 (5H, m), 2.28-2.13 (1H, m),2.12- 2.04 (1H, m), 2.10 and 2.05 (3H, 2 × s), 0.99-0.90 (6H, m), 0.81(3H, t,), 0.73- 0.64 (2H, m), 0.60-0.50 (2H, m) 147

530 9.00 and 8.97 (1H, 2 × d), 8.47 and 8.42 (1H, 2 × d), 7.86 and 7.72(1H, 2 × d), 7.71 and 7.49 (1H, 2 × d), 7.38-7.30 (4H, m), 7.28-7.21(1H, m), 6.72 and 6.71 (1H, 2 × d), 6.63 and 6.62 (1H, 2 × d), 5.20-5.11(1H, m), 3.44-3.37 (1H, m), 3.27-3.19 (1H, m), 3.22 and 3.21 (3H, 2 ×s), 2.92- 2.80 (2H, m), 2.58-2.31 (3H, m), 2.16- 2.04 (1H, m), 2.11 and2.07 (3H, 2 × s), 2.00 (1H, d), 1.88-1.70 (2H, m), 1.69- 1.57 (1H, m),1.54-1.42 (1H, m), 0.74 (3H, d), 0.72-0.65 (2H, m), 0.59-0.52 (2H, m)148

530 8.44 and 8.37 (1H, 2 × d), 8.31 and 8.13 (1H, 2 × d), 7.86 (1H, 2 ×dt), 7.75 and 7.70 (1H, 2 × d), 7.48 and 7.47 (1H, 2 × d), 7.44-7.37(2H, m), 7.35-7.28 (2H, m), 7.25-7.18 (1H, m), 6.77 and 6.75 (1H, 2 ×d), 6.65 and 6.63 (1H, 2 × d), 4.80-4.70 (1H, m), 3.34-3.27 (1H, m),3.20 and 3.20 (3H, 2 × s), 3.17-3.10 (1H, m), 3.06-2.99 (1H, m),2.90-2.80 (1H, m), 2.66-2.54 (1H, m), 2.30-2.10 (2H, m), 2.12 and 2.05(3H, 2 × s), 1.85-1.73 (1H, m), 1.70-1.58 (2H, m), 1.51-1.39 (1H, m),0.744 and 0.734 (3H, 2 × d), 0.71-0.63 (2H, m), 0.59- 0.50 (2H, m) 149

530 8.45 and 8.39 (1H, 2 × s), 8.18 and 7.94 (1H, 2 × d), 7.87 (1H, d),7.76 and 7.70 (1H, 2 × s), 7.52-7.45 (1H, m), 7.43-7.29 (4H, m),7.27-7.18 (1H, m), 6.81-6.74 (1H, m), 6.69-6.62 (1H, m), 4.98-4.87 (1H,m), 3.20 (3H, s), 3.18-3.08 (1H, m), 2.99-2.90 (1H, m), 2.89-2.80 (1H,m), 2.60-2.34 (4H, m), 2.21-1.96 (2H, m), 2.13 and 2.05 (3H, 2 × s),1.86-1.71 (1H, m), 1.69-1.56 (2H, m), 1.53-1.40 (1H, m), 0.90 (3H, s),0.74-0.64 (2H, m), 0.60- 0.50 (2H, m) 150

530 9.02-8.95 (1H, m), 8.50-8.35 (1H, m), 7.90-7.83 (1H, m), 7.74-7.66(1H, m), 7.53-7.44 (1H, m), 7.44-7.16 (5H, m), 6.76-6.58 (2H, m), 4.73and 4.58 (1H, 2 × m), 3.43-3.31 (1H, m), 3.26-3.11 (4H, m), 3.08-2.97(1H, m), 2.93-2.79 (1H, m), 2.6-2.4 (2H, m), 2.30-2.02 (5H, m),1.88-1.59 (3H, m), 1.52-1.38 (1H, m), 0.78-0.62 (5H, m), 0.61-0.48 (2H,m) 151

530 9.08 and 8.87 (1H, 2 × d), 8.45 and 8.40 (1H, 2 × d), 7.86 (1H, dd),7.74 and 7.70 (1H, 2 × d), 7.49 and 7.48 (1H, 2 × d), 7.37- 7.21 (5H,m), 6.72 (1H, d), 6.62 (1H, d), 5.10-5.02 (1H, m), 4.36 (1H, t), 3.18(2H, t), 3.14-3.00 (1H, m), 2.89-2.79 (1H, m), 2.78-2.69 (1H, m), 2.12and 2.05 (3H, 2 × s), 1.96-1.84 (2H, m), 1.80-1.70 (1H, m), 1.69-1.54(2H, m), 1.50-1.37 (1H, m), 1.36-1.21 (2H, m), 0.80 and 0.78 (3H, 2 ×d), 0.72-0.64 (2H, m), 0.59-0.51 (2H, m) 152

516 9.18 and 9.06 (1H, 2 × d), 8.45 and 8.40 (1H, 2 × d), 7.86 (1H, dd),7.74 and 7.70 (1H, 2 × d), 7.49 and 7.47 (1H, 2 × d), 7.38- 7.21 (5H,m), 6.72 (1H, d), 6.62 (1H, d), 5.06 (1H, dd), 4.49 (1H, d), 3.52-3.41(1H, m), 2.93-2.78 (2H, m), 2.62-2.37 (2H, m), 2.25-2.00 (1H, m), 2.11and 2.05 (3H, 2 × s), 1.98-1.45 (6H, m), 0.78 and 0.77 (3H, 2 × d),0.72-0.64 (2H, m), 0.59- 0.51 (2H, m) 153

488 9.14 and 9.09 (1H, 2 × d), 8.45 and 8.40 (1H, 2 × d), 7.86 (1H, d),7.72 (1H, d), 7.48 and 7.48 (1H, 2 × d), 7.40-7.27 (4H, m), 7.26-7.19(1H, m), 6.74-6.68 (1H, m), 6.63-6.58 (1H, m), 5.11-5.02 (1H, m),2.89-2.79 (1H, m), 2.40-2.27 (2H, m), 2.25-2.13 (1H, m), 2.10 and 2.06(3H, 2 × s), 1.01 (9H, s), 0.83 and 0.82 (3H, 2 × d), 0.72-0.64 (2H, m),0.59-0.51 (2H, m) 154

502 8.47 and 8.41 (1H, 2 × d), 8.08, 7.83 and 7.87 (2H, 3 × d), 7.75 and7.73 (1H, 2 × s), 7.49 and 7.48 (1H, 2 × d), 7.38-7.28 (4H, m),7.26-7.18 (1H, m), 6.75 (1H, d), 6.66 and 6.65 (1H, 2 × d), 5.14 and5.05 (1H, 2 × dd), 2.90-2.79 (1H, m), 2.41-2.20 (2H, m), 2.14, 2.11,2.09 and 2.07 (6H, 4 × s), 2.04-1.95 (1H, m), 0.96 and 0.94 (9H, 2 × s),0.84 and 0.81 (3H, 2 × d), 0.73-0.64 (2H, m), 0.59-0.51 (2H, m) 155

503 8.69 and 8.54 (1H, 2 × d), 8.44 and 8.38 (1H, 2 × d), 7.86 (1H, d),7.74 and 7.70 (1H, 2 × d), 7.49 and 7.47 (2 × d, J = 7.9 Hz, 1H),7.41-7.28 (4H, m), 7.26-7.19 (1H, m), 6.75 and 6.74 (1H, 2 × d), 6.63and 6.62 (1H, 2 × d), 5.03 (1H, dd), 2.90- 2.78 (1H, m), 2.42-2.22 (7H,m), 2.12 and 2.05 (3H, 2 × s), 2.09 (6H, s), 0.84 (3H, d), 0.73-0.64(2H, m), 0.59-0.50 (2H, m) 156

517 8.59 and 8.55 (1H, 2 × d), 8.46 and 8.40 (1H, 2 × d), 7.87 (1H, d),7.74 and 7.72 (1H, 2 × d), 7.50 and 7.48 (1H, 2 × d), 7.40- 7.29 (5H,m), 7.28-7.20 (1H, m), 6.751 and 6.747 (1H, 2 × d), 6.65 (1H, d), 5.11-5.03 (1H, m), 2.90-2.80 (1H, m), 2.45- 2.28 (6H, m), 2.20, 2.18, 2.13,2.11, 2.10 and 2.07 (12H, 6 × s), 2.04-1.96 (1H, m), 0.81 (3H, d),0.74-0.64 (2H, m), 0.59- 0.51 (2H, m) 157

502 8.48-8.36 (2H, m), 7.86 (1H, dd), 7.74 and 7.70 (1H, 2 × d), 7.49and 7. (1H, 2 × d), 7.40-7.28 (4H, m), 7.26-7.18 (1H, m), 6.74 (1H, d),6.63 and 6.62 (1H, 2 × d), 5.11-5.03 (1H, m), 2.91-2.78 (1H, m),2.41-2.02 (5H, m), 2.11 and 2.05 (3H, 2 × s), 0.88 (9H, s), 0.85 (3H,d), 0.74-0.63 (2H, m), 0.59-0.50 (2H, m)

Example 158

N-Methoxy-4-methyl-3-[3-[[(1R,2S)-2-methyl-1-(1-naphthalenyl)-3-(1-pyrrolidinyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

a)4-Methyl-3-[3-[[(1R,2R)-2-methyl-1-(1-naphthalenyl)-3-oxopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzoicacid, methyl ester

The subtitle compound was prepared from3-[3-[[(1R,2R)-3-hydroxy-2-methyl-1-(1-naphthalenyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoicacid, methyl ester (Example 137a) using the method described in Example138a.

b)4-Methyl-3-[3-[[(1R,2S)-2-methyl-1-(1-naphthalenyl)-3-(1-pyrrolidinyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzoicacid, methyl ester

The subtitle compound was prepared from4-methyl-3-[3-[[(1R,2R)-2-methyl-1-(1-naphthalenyl)-3-oxopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzoicacid, methyl ester (Example 158a) using the method described in theExample 138b.

MS: APCI(+ve) 511 (M+H⁺).

¹H NMR δ (DMSO-d₆, 400 MHz) 8.53-8.21 (2H, m), 8.03-7.75 (4H, m),7.66-7.43 (6H, m), 6.75-6.57 (2H, m), 6.19-6.04 (1H, m), 3.87 and 3.84(3H, s), 2.50-2.39 (6H, m), 2.29-2.18 (1H, m), 2.17 and 2.08 (3H, 2×s),2.50-2.39 (6H, m), 1.82-1.68 (4H, m), 0.82 and 0.80 (3H, 2×d).

c)N-Methoxy-4-methyl-3-[3-[[(1R,2S)-2-methyl-1-(1-naphthalenyl)-3-(1-pyrrolidinyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

A solution of iso-propylmagnesium chloride (2M in diethyl ether, 1.2 mL)was added dropwise to a stirred mixture of4-methyl-3-[3-[[(1R,2S)-2-methyl-1-(1-naphthalenyl)-3-(1-pyrrolidinyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzoicacid, methyl ester (Example 158b, 90 mg), O-methylhydroxylaminehydrochloride (65 mg) and tetrahydrofuran (2 mL) at room temperature.After 15 min the reaction was quenched with sat. aqueous NH₄Cl andextracted into ethyl acetate. The organic phase was dried (Na₂SO₄),filtered and concentrated in vacuo. Purification by preparative HPLC(Gemini column, 0.1% ammonia: acetonitrile eluent) afforded the titlecompound as a solid (65 mg).

MS: APCI(+ve) 526 (M+H⁺).

¹H NMR δ (DMSO-d₅, 400 MHz) 11.81 and 11.75 (1H, 2×s), 8.40 (1H, dd),8.57-8.18 (1H, m), 7.95 (1H, d), 7.83 (1H, d), 7.79 (1H, dd), 7.70-7.48(6H, m), 6.72 and 6.70 (1H, 2×d), 6.66-6.63 (1H, m), 6.16-6.06 (1H, m),3.71 and 3.68 (3H, 2×s), 2.64-2.40 (4H, br), 2.27-2.11 (1H, br), 2.14and 2.05 (3H, 2×s), 1.82-1.68 (4H, br), 0.89-0.77 (3H, br).

The following Examples 159-161 (Table 4) were prepared fromcorresponding alcohols (Examples 136c or 137a) and amines using themethod described for Example 158.

Example 159

N-Methoxy-4-methyl-3-[3-[[(1R,2S)-2-methyl-1-phenyl-3-(1-pyrrolidinyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 160

N-Methoxy-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-(4-morpholinyl)-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 161

N-Methoxy-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-(4-morpholinyl)-1-(1-naphthalenyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

TABLE 4

MS [M + H]⁺ Example R m/z ¹H NMR δ (DMSO-d₆) 159

476 11.84 and 11.76 (1H, 2 × s), 9.46-9.29 (1H, m), 7.79 (1H, d), 7.69and 7.64 (1H, 2 × s), 7.60-7.22 (5H, m), 6.84 and 6.83 (1H, 2 × d), 6.76and 6.75 (1H, 2 × d), 5.23-5.09 (1H, m), 3.71 and 3.68 (3H, 2 × s),3.64-3.48 (2H, m), 3.19-2.77 (3H, m), 2.65-2.54 (1H, m), 2.16 and 2.08(3H, 2 × s), 2.01-1.78 (5H, m), 1.06 and 1.05 (3H, 2 × d) 160

492 9.24 and 9.09 (1H, 2 × d), 7.79 (1H, d), 7.65 and 7.61 (1H, 2 × d),7.52 and 7.51 (1H, 2 × d), 7.38-7.21 (6H, m), 6.73 (1H, d), 6.643 and6.639 (1H, 2 × d), 5.07 (1H, dd), 3.81-3.59 (4H, m), 3.71 and 3.69 (3H,2 × s), 2.35-2.22 (3H, m), 2.21-2.09 (1H, m), 2.12 and 2.07 (3H, 2 × s),1.98 (1H, dd), 0.79 and 0.78 (3H, 2 × d) 161

542 11.81 and 11.75 (1H, 2 × s), 8.49-8.18 (2H, m), 7.95 (1H, d), 7.83(1H, d), 7.79 (1H, dd), 7.70-7.48 (6H, m), 6.72 and 6.70 (1H, 2 × d),6.65 and 6.645 (1H, 2 × d), 6.21-6.13 (1H, m), 3.75-3.60 (4H, m), 3.71and (3H, 2 × s), 2.61- 2.42 (4H, m), 2.42-2.26 (2H, m), 2.14 and 2.06(3H, 2 × s), 2.07 (1H, m), 0.80 and 0.78 (3H, 2 × d)

Example 162

3-[3-[[(1R,2R)-3-Hydroxy-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-methoxy-4-methyl-benzamide,trifluoroacetate

A solution of iso-propylmagnesium chloride (2M in tetrahydrofuran, 5.5mL) was added dropwise to a stirred mixture of3-[3-((1R,2R)-3-hydroxy-2-methyl-1-phenylpropylamino)-2-oxo-2H-pyrazin-1-yl]-4-methyl-benzoicacid, methyl ester (Example 136c, 374 mg), O-methylhydroxylaminehydrochloride (200 mg) and tetrahydrofuran (5 mL) at 0° C. After 15 minthe reaction was quenched with sat. aqueous NH₄Cl and extracted intoethyl acetate. The organic phase was dried (Na₂SO₄), filtered andconcentrated in vacuo to give a crude title product (392 mg).Purification by preparative HPLC (Gemini column, 0.1% TFA: acetonitrileeluent) afforded the title compound.

MS: APCI(+ve) 423 (M+H⁺)

¹H NMR δ (DMSO-d₆, 400 MHz) 11.77 (1H, m), 7.78 (1H, d), 7.68 and 7.62(1H, 2×s), 7.51 (1H, t), 7.42 (2H, t), 7.33 (2H, t), 7.24 (1H, t),6.80-6.75 (1H, m), 6.71-6.66 (1H, m), 5.04-4.97 (1H, m), 3.71 and 3.68(3H, 2×s), 3.23-3.12 (2H, m), 2.31-2.20 (1H, m), 2.14 and 2.07 (3H,2×s), 0.88 (3H, d).

Example 163

N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Potassium carbonate (330 mg) and 1-bromo-2-chloroethane (0.2 mL) wereadded to a stirred solution ofN-cyclopropyl-3-(3-(2-(2-hydroxyphenyl)propan-2-ylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzamide(Example 134, 0.1 g) in acetonitrile (5 mL). The reaction mixture wasstirred under nitrogen at 83° C. for 16 h then concentrated in vacuo.The residue was treated with water and extracted into dichloromethane.The organic phase was washed with brine, dried (Na₂SO₄), filtered andconcentrated in vacuo. The residue (120 mg) was treated with 33%methylamine in ethanol (3 mL) and heated within a microwave at 100° C.for 60 minutes. The mixture was concentrated in vacuo. Purification bypreparative HPLC (Gemini column, 0.1% ammonia: acetonitrile eluent)afforded the title compound as a solid (65 mg).

MS: APCI(+ve) 476 (M+H⁺).

¹H NMR δ (DMSO-d₆, 400 MHz) 8.43 (1H, d), 7.86 (1H, dd), 7.72 (1H, d),7.48 (1H, d), 7.35 (1H, dd), 7.22-7.17 (1H, m), 6.97 (1H, d), 6.94-6.85(2H, m), 6.67 (1H, d), 6.63 (1H, d), 4.04-3.92 (2H, m), 2.89-2.80 (3H,m), 2.28 (3H, s), 2.09 (3H, s), 1.83 (6H, s), 0.71-0.66 (2H, m),0.57-0.52 (2H, m).

Example 164

N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[3-(methylamino)propoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

The title compound was prepared fromN-cyclopropyl-3-(3-(2-(2-hydroxyphenyl)propan-2-ylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzamide(Example 134) and 1-bromo-3-chloropropane using the method described forExample 163.

MS: APCI(+ve) 490 (M+H+).

¹H NMR δ (DMSO-d₆, 400 MHz) 8.43 (1H, d), 7.86 (1H, dd), 7.73 (1H, d),7.48 (1H, d), 7.35 (1H, dd), 7.23-7.17 (1H, m), 6.98-6.88 (3H, m), 6.67(1H, d), 6.64 (1H, d), 4.05-3.93 (2H, m), 2.88-2.39 (2H, m), 2.34 (3H,s), 2.10 (3H, s), 2.00-1.91 (2H, m), 1.85 (3H, s), 1.83 (3H, s),0.72-0.67 (2H, m), 0.57-0.53 (2H, m).

Example 165

N-Cyclopropyl-4-methyl-3-[2-oxo-3-[[(1R)-1-[2-[2-(1-pyrrolidinyl)ethoxy]phenyl]propyl]amino]-1(2H)-pyrazinyl]-benzamide

a)(S)-2-Methyl-N-[(1R)-1-[2-(2-hydroxyethoxy)phenyl]propyl]-2-propanesulfinamideand(S)-2-methyl-N-[(1S)-1-[2-(2-hydroxyethoxy)phenyl]propyl]-2-propanesulfinamide

(S)-2-Methyl-2-propanesulfinamide (398 mg) and anhydrous copper (II)sulphate (1.15 g) were added to a stirred solution of2-(2-hydroxyethoxy)-benzaldehyde (0.5 g) in dichloromethane (15 mL). Thereaction mixture was stirred for 72 h then filtered and concentrated invacuo. The residue was treated with dichloromethane (15 mL) and cooledto −78° C. A solution of ethylmagnesium chloride in tetrahydrofuran (2M,4.5 mL) was added dropwise. The mixture was stirred at −78° C. for 1 hand allowed to warm to −10° C. over two h, then was quenched withsaturated NH₄Cl solution. The mixture was extracted withdichloromethane. The pooled organics were washed with brine, dried(Na₂SO₄), filtered and concentrated in vacuo. Purification (SiO₂chromatography eluting with 1:1 ethyl acetate/iso-hexane) afforded bothsubtitle compounds.

(S)-2-Methyl-N-[(1R)-1-[2-(2-hydroxyethoxy)phenyl]propyl]-2-propanesulfinamide(330 mg)

¹H NMR δ (DMSO-d₆, 400 MHz) 7.29 (1H, dd), 7.20-7.15 (1H, m), 6.96-6.88(2H, m), 5.17 (1H, d), 4.90 (1H, t), 4.53 (1H, d), 4.04-3.93 (2H, m),3.73 (2H, q), 1.86-1.67 (2H, m), 1.05 (9H, s), 0.82 (3H, t).

S)-2-Methyl-N-[(1S)-1[2-(2-hydroxyethoxy)phenyl]propyl]-2-propanesulfinamide (360 mg

¹H NMR δ (DMSO-d₆, 400 MHz) 7.32 (1H, dd), 7.21-7.16 (1H, m), 6.97-6.87(2H, m), 5.35 (1H, d), 4.92 (1H, t), 4.43-4.37 (1H, m), 4.06-3.95 (2H,m), 3.73 (2H, q), 1.81-1.62 (2H, m), 1.11 (9H, s), 0.82 (3H, t).

b)N-Cyclopropyl-3-[3-[[(1R)-1-[2-(2-hydroxyethoxy)phenyl]propyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

A mixture of(S)-2-methyl-N-[(1R)-1-[2-(2-hydroxyethoxy)phenyl]propyl]-2-propanesulfinamide(Example 165a, 330 mg), methanol (10 mL) and a solution of hydrogenchloride in 1,4-dioxane (4M, 4 mL) was stirred at room temperature for17 h. The mixture was concentrated in vacuo. The residue was treatedwith 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methylester (Example 1b, 400 mg), triethylamine (0.92 mL) and tetrahydrofuran(5 mL). The mixture was stirred at room temperature for 5 days beforethe addition of cyclopropylamine (0.5 mL) and cyclopentylmagnesiumbromide (2M in diethyl ether, 5 mL) dropwise. The mixture was stirredfor 15 min., quenched with saturated NH₄Cl solution and extracted intoethyl acetate. The pooled organics were washed with brine, dried(Na₂SO₄), filtered and concentrated in vacuo. The residue was treatedwith ethanol (5 mL) was added followed by the addition of ammoniumformate (0.42 g) and 10% palladium on carbon (60 mg). The reactionmixture was heated within a microwave for 2 h at 100° C. before beingcooled to room temperature, filtered and washed with ethanol. Thefiltrate was concentrated in vacuo. The residue was treated withdichloromethane and washed with brine, dried (Na₂SO₄), filtered andconcentrated in vacuo to give the crude product (410 mg) that was usedin the next step without purification.

c)N-Cyclopropyl-4-methyl-3-[2-oxo-3-[[(1R)-1-[2-[2-(1-pyrrolidinyl)ethoxy]phenyl]propyl]amino]-1(2H)-pyrazinyl]-benzamide

Methanesulfonyl chloride (0.21 mL) was added to a stirred solution ofN-cyclopropyl-3-[3-[[(1R)-1-[2-(2-hydroxyethoxy)phenyl]propyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide(410 mg) and triethylamine (0.5 mL) in dichloromethane (10 mL) at 0° C.The mixture was stirred for 1 h at 0° C. and 1 h at room temperature.Water was added and the organic phase was separated, (Na₂SO₄), filteredand concentrated in vacuo. The residue was treated with dichloromethane(10 mL) and pyrrolidine (0.73 mL) and the mixture was stirred at roomtemperature for 24 h. The mixture was concentrated in vacu. Purificationby preparative HPLC (Gemini column, 0.1% ammonia: acetonitrile eluent)afforded the title compound as a solid (147 mg).

MS: APCI(+ve) 516 (M+H⁺).

¹H NMR δ (DMSO-d₆, 400 MHz) 8.44 (0.5H, d), 8.40 (0.5H, d), 7.88-7.84(1H, m), 7.77 (0.5H, d), 7.71 (0.5H, d), 7.51-7.46 (1H, m), 7.40-7.35(1H, m), 7.31-7.25 (1H, m), 7.23-7.17 (1H, m), 7.03-6.98 (1H, m),6.92-6.86 (1H, m), 6.81-6.78 (1H, m), 6.69-6.65 (1H, m), 5.26-5.19 (1H,m), 4.15-4.08 (2H, m), 2.88-2.80 (3H, m), 2.60-2.52 (4H, m), 2.13 (1.5H,s), 2.07 (1.5H. s), 1.90-1.79 (2H, m), 1.71-1.65 (4H, m), 0.89-0.82 (3H,m), 0.72-0.64 (2H, m), 0.58-0.51 (2H, m).

Example 166

N-Cyclopropyl-4-methyl-3-[2-oxo-3-[[(1S)-1-[2-[2-(1-pyrrolidinyl)ethoxy]phenyl]propyl]amino]-1(2H)-pyrazinyl]-benzamide

The title compound was prepared from(S)-2-methyl-N-[(1S)-1-[2-(2-hydroxyethoxy)phenyl]propyl]-2-propanesulfinamide(Example 165a) using the method described for Example 165b and 165c.

MS: APCI(+ve) 516 (M+H⁺).

¹H NMR δ (DMSO-d₆, 400 MHz) 8.44 (0.5H, d), 8.40 (0.5H, d), 7.88-7.84(1H, m), 7.77 (0.5H, d), 7.71 (0.5H, d), 7.51-7.46 (1H, m), 7.40-7.35(1H, m), 7.31-7.25 (1H, m), 7.23-7.17 (1H, m), 7.03-6.98 (1H, m),6.92-6.86 (1H, m), 6.80 (1H, t), 6.67 (1H, dd), 5.26-5.18 (1H, m),4.16-4.08 (2H, m), 2.89-2.79 (3H, m), 2.61-2.52 (4H, m), 2.13 (1.5H, s),2.07 (1.5H, s), 1.90-1.78 (2H, m), 1.72-1.64 (4H, m), 0.89-0.82 (3H, m),0.72-0.64 (2H, m), 0.59-0.51 (2H, m).

Example 167

N-Cyclopropyl-4-methyl-3-[3-[[1-[2-[2-(methylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

a) 1-(2-(Benzyloxy)phenyl)cyclopropanamine

Titanium(IV) isopropoxide (1.62 mL) was added to a stirred solution of2-(benzyloxy)benzonitrile (1.05 g) in diethyl ether (25 mL) cooled to−78° C. under N₂ followed by the dropwise addition of ethylmagnesiumbromide (3.67 mL of a 3M solution in diethylether). The resultingmixture was stirred at −78° C. for 10 min and then warmed to rt over 1h. Boron trifluoride diethyl etherate (1.27 mL) was added dropwise andthe mixture was stirred for 1 h. The reaction was quenched with 1M HCl(30 mL). Diethyl ether (30 mL) was added and the organic layerseparated. To the aqueous layer was added aqueous 10% NaOH (50 mL) anddiethyl ether and this was filtered through celite to remove solids(which were washed with further diethyl ether). This mixture wasextracted with diethyl ether (2×70 mL) and dichloromethane (70 mL). Allthe organic layers were combined, dried (Na₂SO₄) and the solventsremoved in vacuo. The residue was dissolved in dichloromethane and andloaded on to an 10 g SCX cartridge. The impurities were washed throughwith methanol (50 mL) and discarded. Elution with 7N methanolic ammonia(25 mL) and evaporation in vacuo gave the subtitle compound as a brownoil (0.625 g).

¹H NMR δ (CDCl₃) 7.47 (d, 2H), 7.40 (t, 2H), 7.33 (t, 1H), 7.26-7.20 (m,2H), 6.95 (d, 1H), 6.90 (td, 1H), 5.18 (s, 2H), 1.07 (dd, 2H), 0.89 (dd,3H).

b) Methyl3-(3-(1-(2-(benzyloxy)phenyl)cyclopropylamino)-5-bromo-2-oxopyrazin-1(2H)-yl)-4-methylbenzoate

To 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methylester (Example 1 b, 0.7 g) in THF (3 mL) was added1-(2-(Benzyloxy)phenyl)cyclopropanamine (Example 167a, 0.625 g) andN,N-diisopropylamine (0.43 mL) and the reaction heated within a CEMDiscover microwave at 120° C. for 80 min within a sealed 10 mL microwavevial. After cooling to rt, the organics were washed with water, dried(Na₂SO₄), filtered and the crude product purified (SiO₂ chromatographyeluting with 50-100% dichloromethane in iso-hexane) to afford thesubtitle product as an orange foam (0.62 g).

¹H NMR δ (DMSO-d₆) 7.94 (dd, 1H), 7.85 (d, 1H), 7.55-7.51 (m, 5H), 7.35(t, 2H), 7.29 (t, 1H), 7.20 (td, 1H), 7.03 (d, 1H), 7.01 (s, 1H), 6.89(td, 1H), 5.22 (s, 2H), 3.83 (s, 3H), 2.12 (s, 3H), 1.27-1.08 (m, 4H).

c) Methyl3-(3-(1-(2-hydroxyphenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzoate

To Methyl3-(3-(1-(2-(benzyloxy)phenyl)cyclopropylamino)-5-bromo-2-oxopyrazin-1(2H)-yl)-4-methylbenzoate(Example 167b, 543 mg) in ethanol (15 mL) was added ammonium formate(855 mg) and 10% Pd/C (103 mg) and the reaction was heated at 75° C. for1 h. The mixture was filtered through celite and the solids washed withethanol. The filtrate was collected and the volatiles removed in vacuoto give a pale yellow solid. dichloromethane and water were added andthe organic layer separated. The aqueous layer was further extractedwith dichloromethane and ethyl acetate. The combined organic extractswere dried (Na₂SO₄) and the solvent removed in vacuo to give thesubtitle product an off white foam (331 mg).

¹H NMR δ (DMSO-d₆) 11.26 (s, 1H), 8.45 (s, 1H), 7.95 (d, 1H), 7.85 (s,1H), 7.56 (d, 1H), 7.45 (d, 1H), 7.11 (t, 1H), 6.88 (d, 1H), 6.80-6.73(m, 3H), 3.84 (s, 3H), 3.31 (s, 2H), 2.12 (s, 3H), 1.11-1.03 (m, 2H),1.30-1.22 (m, 2H).

d)N-Cyclopropyl-3-(3-(1-(2-hydroxyphenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzamide

To cyclopropylamine (0.60 mL, 8.46 mmol) and Methyl3-(3-(1-(2-hydroxyphenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzoate(Example 167c, 0.331 g) in THF (5 mL) at rt was added isopropylmagnesiumchloride (0.85 mL of a 2M solution in THF) dropwise. The reaction wasstirred for 1 h and then further isopropylmagnesium chloride (0.85 mL of2M solution in THF) was added and the reaction stirred for 16 h. Waterand 2M aqueous HCl were cautiously added and the aqueous layer extractedwith dichloromethane (2x). The combined organics were dried (Na₂SO₄) andthe solvent removed in vacuo to give the subtitle product as a yellowsolid (0.342 g).

¹H NMR δ (DMSO-d₆) 11.15 (s, 1H), 8.47 (s, 1H), 8.36 (d, 1H), 7.85 (dd,1H), 7.71 (d, 1H), 7.47 (d, 1H), 7.46 (dd, 1H), 7.11 (dt, 1H), 6.89 (d,1H), 6.80-6.73 (m, 3H), 2.87-2.79 (m, 1H), 2.09 (s, 3H), 1.30-1.21 (m,2H), 1.14-1.04 (m, 2H), 0.70-0.64 (m, 2H), 0.55-0.51 (m, 2H).

e)3-(3-(1-(2-(2-Chloroethoxy)phenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-4-methylbenzamide

ToN-Cyclopropyl-3-(3-(1-(2-hydroxyphenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzamide(Example 167d, 0.34 g) in acetonitrile (5 mL) under nitrogen was addedpotassium carbonate (1.13 g) followed by 1-bromo-2-chloroethane (1.35mL) and the reaction heated at 95° C. for 15 h. After cooling to rt themixture was filtered through celite, and the solid cake washed withfurther acetonitrile. The filtrates were collected and the solventsremoved in vacuo to give the subtitle product as a brown-orange solid(0.373 g).

¹H NMR δ (DMSO-d₆) 8.35 (d, 1H), 7.84 (dd, 1H), 7.67 (d, 1H), 7.52 (dd,1H), 7.46 (d, 1H), 7.25 (s, 1H), 7.21 (dt, 1H), 6.97 (d, 1H), 6.90 (t,1H), 6.87 (d, 1H), 6.71 (d, 1H), 4.31 (t, 2H), 4.00 (t, 2H), 2.86-2.78(m, 1H), 2.05 (s, 3H), 1.26-1.06 (m, 4H), 0.69-0.64 (m, 2H), 0.55-0.50(m, 2H).

f)N-Cyclopropyl-4-methyl-3-(3-(1-(2-(2-(methylamino)ethoxy)phenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)benzamide

To3-(3-(1-(2-(2-Chloroethoxy)phenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-4-methylbenzamide(Example 167e, 100 mg) in a 10 mL microwave vial was added methylamine(2 mL of a 33% solution in ethanol). This was sealed and heated within aCEM Discover microwave for 30 min at 100° C. The volatiles were removedin vacuo and the residue taken up in methanol and purified bypreparative HPLC (ACE column, 0.1% TFA: acetonitrile eluent) affordedthe title compound. This was dissolved in acetonitrile and filteredthrough SCX resin eluting with acetonitrile and methanol (discarded)followed by 7N NH₃ in methanol. The basic fractions were collected andthe volatiles were removed in vacuo. Trituration with diethyl etherafforded the title product as a white solid (46 mg).

MS: APCI(+ve) 474 (M+H)⁺.

¹H NMR δ (DMSO-d₆) 8.35 (d, 1H), 7.84 (dd, 1H), 7.68 (d, 1H), 7.53-7.49(m, 2H), 7.46 (d, 1H), 7.19 (td, 1H), 6.96 (d, 1H), 6.86 (t, 1H), 6.86(d, 1H), 6.69 (d, 1H), 4.08 (t, 2H), 2.95 (t, 2H), 2.86-2.79 (m, 1H),2.39 (s, 3H), 2.06 (s, 3H), 1.20-1.01 (m, 4H), 0.69-0.64 (m, 2H),0.55-0.50 (m, 2H).

Example 168

N-Cyclopropyl-4-methyl-3-[3-[[1-[2-[2-(ethylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

The title product was prepared from3-(3-(1-(2-(2-chloroethoxy)phenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-4-methylbenzamide(Example 167e) and ethylamine (70% in water) in ethanol as co-solventusing a similar method to that described for example 167f.

MS: APCI(+ve) 488 (M+H)⁺.

¹H NMR δ (DMSO-d₆) 8.35 (d, 1H), 7.84 (d, 1H), 7.68 (s, 1H), 7.50-7.41(m, 3H), 7.19 (t, 1H), 6.95 (d, 1H), 6.88-6.83 (m, 2H), 6.70 (d, 1H),4.05 (t, 2H), 2.94 (t, 2H), 2.88-2.77 (m, 1H), 2.62 (q, 2H), 2.06 (s,3H), 1.22-0.97 (m, 4H), 0.99 (t, 3H), 0.70-0.64 (m, 2H), 0.54-0.49 (m,2H).

Example 169

N-Cyclopropyl-3-fluoro-4-methyl-5-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

a) 3-Fluoro-4-methyl-5-nitro-benzoic acid, ethyl ester

To ethyl 3-amino-4-methyl-5-nitrobenzoate (J. Chem. Soc. 1960, 672-6; 5g) solid at 0° C. was added ice cooled 48% aqueous tetrafluoroboric acid(35 mL) slowly (exotherm) and the mixture stirred for 5 min. Sodiumnitrite (1.69 g) was added and the mixture stirred for 1 h then furthertetrafluoroboric acid (15 mL) was added. After 1 h the precipitate wasfiltered off (caution—potentially explosive), washed with water anddiethyl ether to afford a solid (1.27 g). This was diluted with solidsand and heated at 130° C. for 1 h (gas evolution observed). Aftercooling to rt, dichloromethane (30 mL) was added and the solids filteredoff. The filtrate was collected and the solvent removed in vacuo toafford the crude product an oil. This was combined with the crudeproduct from an identical reaction carried out on ⅕ scale and purified(SiO₂ chromatography eluting with iso-hexane) to afford the subtitleproduct as an yellow solid (1.43 g).

¹H NMR δ (CDCl₃) 8.37 (s, 1H), 7.94 (dd, 1H), 4.43 (q, 2H), 2.53 (d,3H), 1.42 (t, 3H).

b) 3-Amino-5-fluoro-4-methyl-benzoic acid, ethyl ester

3-Fluoro-4-methyl-5-nitro-benzoic acid, ethyl ester (Example 169a, 1.43g) in ethanol (30 mL) was pumped continuously through a Pd/C cartridgefor 4 h under an atmosphere of hydrogen. The solvents were removed togive the subtitle product (1.20 g) as a solid.

¹H NMR δ (CDCl₃) 7.15 (s, 1H), 7.13 (d, 1H), 4.34 (q, 2H), 3.81 (s, 2H),2.10 (d, 3H), 1.37 (t, 3H).

c) 3-[(Cyanomethyl)amino]-5-fluoro-4-methyl-benzoic acid, ethyl ester

To a stirred solution of 3-amino-5-fluoro-4-methyl-benzoic acid, ethylester (Example 169b, 1.2 g) in THF (10 mL) at room temperature was addedN-ethyldiisopropylamine (1.28 mL) followed by bromoacetonitrile (0.51mL) and the reaction was heated at reflux for 14 h. Additionalbromoacetonitrile (0.21 mL) was added and the mixture was heated atreflux for 6 h. Further bromoacetonitrile (0.21 mL) was added andheating was continued for a further 12 h. After cooling to roomtemperature the reaction was concentrated. Aqueous HCl (30 mL, 1 N) andethyl acetate (30 mL) were added. The layers were separated and theorganic fraction was dried (Na₂SO₄), filtered and concentrated to givethe subtitle product (1.43 g) as a solid.

¹H NMR δ (CDCl₃) 7.30 (d, 1H), 7.17 (s, 1H), 4.38 (q, 2H), 4.24 (s, 2H),4.03 (s, 1H), 2.12 (s, 3H), 1.40 (t, 3H).

d) 3-(3,5-Dibromo-2-oxo-1(2H)-pyrazinyl)-5-fluoro-4-methyl-benzoic acid,ethyl ester

To a stirred suspension of3-[(cyanomethyl)amino]-5-fluoro-4-methyl-benzoic acid, ethyl ester(Example 169c, 1.43 g) in dichloromethane (13 mL) under nitrogen at roomtemperature was added DMF (0.04 mL) and oxalyl bromide (1.70 mL)dropwise over 5 min. After stirring at room temperature for 6 h furtheroxalyl bromide (0.85 mL) and DMF (0.04 mL) were added and the reactionstirred for 14 h. The mixture was concentrated in vacuo (caution:volatiles contain oxalyl bromide). The residue was purified (SiO₂chromatography eluting with dichloromethane) to afford the subtitleproduct (1.23 g).

¹H NMR δ (DMSO-d₆) 8.11 (s, 1H), 7.93 (s, 1H), 7.84 (dd, 1H), 4.34 (q,2H), 2.10 (d, 3H), 1.32 (t, 3H).

e)3-[5-Bromo-3-[[1-methyl-1-[2-(phenylmethoxy)phenyl]ethyliamino]-2-oxo-1(2H)-pyrazinyl]-5-fluoro-4-methyl-benzoicacid, ethyl ester

3-(3,5-Dibromo-2-oxo-1(2H)-pyrazinyl)-5-fluoro-4-methyl-benzoic acid,ethyl ester (Example 169d, 1.137 g, 2.62 mmol) was dissolved in dioxane(10 mL). a, a-Dimethyl-2-(phenylmethoxy)-benzenemethanamine (Example134a, 0.63 g) and N-ethyldiisopropylamine (0.67 mL, 3.93 mmol) wereadded under nitrogen and the resulting solution was stirred at 100° C.for 10 h. The reaction mixture was diluted with water (50 mL), andextracted with ethyl acetate (100 mL x 2). The combined organics weredried (MgSO₄), filtered and evaporated to afford the crude product. Thiswas purified by (SiO₂ chromatography eluting with dichloromethane) toafford the subtitle product (1.55 g).

MS: APCI(+ve) 595 (M+H)⁺.

f)3-[5-Bromo-3-[[1-methyl-1-[2-(phenylmethoxy)phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-5-fluoro-4-methyl-benzamide

Cyclopropylamine (1.86 mL) was added to3-[5-bromo-3-[[1-methyl-1-[2-(phenylmethoxy)phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-5-fluoro-4-methyl-benzoicacid, ethyl ester (Example 169e, 1.6 g) in THF (24 mL) under nitrogen atroom temperature and isopropylmagnesium chloride (5.28 mL of a 2Msolution in THF) was then added dropwise over 10 min. The resultingsolution was stirred at 75° C. for 16 h. After cooling to roomtemperature, the solution was acidified with 2M HCl and extracted intodichloromethane. The organic fractions were concentrated in vacuo togive the subtitle compound (0.7g).

¹H NMR δ (DMSO-d₆) 8.51 (d, 1H), 7.74 (d, 1H), 7.67 (s, 1H), 7.43 (dd,2H), 7.37-7.29 (m, 4H), 7.26-7.21 (m, 1H), 7.15 (s, 1H), 7.08 (d, 1H),6.99 (s, 1H), 6.95 (t, 1H), 5.13 (s, 2H), 2.90-2.81 (m, 1H), 1.97 (d,3H), 1.84 (s, 6H), 0.76-0.67 (m, 2H), 0.58-0.53 (m, 2H).

MS: APCI(+ve) 605 (M+H)⁺.

g)N-Cyclopropyl-3-fluoro-5-[3-[[1-(2-hydroxyphenyl)-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

The title product was prepared from3-[5-bromo-3-[[1-methyl-1-[2-(phenylmethoxy)phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-5-fluoro-4-methyl-benzamide(Example 169f, 0.7 g) using a similar hydrogenation method to thatdescribed for example 167c.

MS: APCI(+ve) 437 (M+H)⁺.

h)3-[3-[[1-[2-(2-Chloroethoxy)phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-5-fluoro-4-methyl-benzamide

The title product was prepared fromN-cyclopropyl-3-fluoro-5-[3-[[1-(2-hydroxyphenyl)-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide(Example 169g, 0.33 g) and 1-bromo-2-chloroethane using a similar methodto that described for example 167e.

MS: APCI(+ve) 500 (M+H)⁺.

i)N-Cyclopropyl-3-fluoro-4-methyl-5-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

The title product was prepared from3-[3-[[1-[2-(2-chloroethoxy)phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-5-fluoro-4-methyl-benzamide(Example 169h) and methylamine using a similar method to that describedfor example 167f. Purification was by RPHPLC (0.2% ammonia/MeCN gradienton a Phenominex column).

¹H NMR δ (DMSO-d₆) 8.52 (d, 1H), 7.75 (d, 1H), 7.64 (s, 1H), 7.34 (d,1H), 7.34 (dd, 1H), 7.19 (t, 1H), 6.98-6.87 (m, 3H), 6.68 (s, 2H),4.03-3.89 (m, 2H), 2.90-2.79 (m, 3H), 2.26 (s, 3H), 1.99 (d, 3H), 1.83(s, 6H), 0.73-0.67 (m, 2H), 0.58-0.52 (m, 2H).

MS: APCI(+ve) 494 (M+H)⁺.

The following Examples 170-197 (Table 5) were prepared from thecorresponding alcohol (Example 136d) and amines using the methodsdescribed for Example 138.

Example 170

N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-(4-methyl-1-piperidinyl)-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 171

N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-[4-(1-methylethyl)-1-piperazinyl]-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 172

N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-1-phenyl-3-(1-piperazinyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 173

N-Cyclopropyl-3-[3-[[(1R,2S)-3-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 174

N-Cyclopropyl-3-[3-[[(1R,2S)-3-(4-fluoro-1-piperidinyl)-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 175

N-Cyclopropyl-3-[3-[[(1R,2S)-3-(4,4-difluoro-1-piperidinyl)-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 176

N-Cyclopropyl-3-[3-[[(1R,2S)-3-[4-(dimethylamino)-1-pipendinyl]-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 177

N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-1-phenyl-3-[4-(trifluoromethyl)-1-piperidinyl]propyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 178

N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-(3-oxo-1-piperazinyl)-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 179

N-Cyclopropyl-3-[3-[[(1R,2S)-3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 180

N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-[(3R)-3-methyl-1-piperazinyl]-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 181

N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-[(3S)-3-methyl-1-piperazinyl]-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 182

N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-[(2-methylpropyl)amino]-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 183

N-Cyclopropyl-3-[3-[[(1R,2S)-3-(cyclopropylamino)-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 184

N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-[(2R)-2-methyl-1-pyrrolidinyl]-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 185

N-Cyclopropyl-3-[3-[[(1R,2S)-3-[(3S)-3-hydroxy-1-piperidinyl]-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 186

N-Cyclopropyl-3-[3-[[(1R,2S)-3-[(3R)-3-hydroxy-1-piperidinyl]-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 187

N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-[(2R)-2-methyl-1-piperazinyl]-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 188

N-Cyclopropyl-3-[3-[[(1R,2S)-3-(2,7-diazaspiro[3.5]non-7-yl)-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 189

N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-1-phenyl-3-(4-thiomorpholinyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 190

N-Cyclopropyl-3-[3-[[(1R,2S)-3-[(3S)-3-hydroxy-1-pyrrolidinyl]-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 191

N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-1-phenyl-3-[4-(tetrahydro-1,1-dioxido-3-thienyl)-1-piperazinyl]propyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 192

1-[(2S,3R)-3-[[4-[5-[(cyclopropylamino)carbonyl]-2-methylphenyl]-3,4-dihydro-3-oxopyrazinyl]amino]-2-methyl-3-phenylpropyl]-4-piperidinecarboxamide

Example 193

N-Cyclopropyl-3-[3-[[(1R,2S)-3-[(2-hydroxy-1,1-dimethylethyl)amino]-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 194

N-Cyclopropyl-3-[3-[[(1R,2S)-3-[(3R,5S)-3,5-dimethyl-1-piperazinyl]-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 195

N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-1-phenyl-3-(4-piperidinylamino)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 196

N-Cyclopropyl-4-methyl-3-[3-[[(1R,2S)-2-methyl-3-(5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 197

N-Cyclopropyl-3-[3-[[(1R,2S)-3-(2,2-dimethyl-1-pyrrolidinyl)-2-methyl-1-phenylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

TABLE 5

MS [M + H]⁺ Example R m/z ¹H NMR δ (DMSO-d₆ or as indicated) 170

514 9.09 and 8.87 (1H, 2 × d), 8.45 and 8.40 (1H, 2 × d), 7.88-7.84 (1H,m), 7.74 and 7.70 (1H, 2 × d), 7.49 and 7.48 (1H, 2 × d), 7.37-7.20 (5H,m), 6.72 (1H, d), 6.62 (1H, d), 5.10-5.03 (1H, m), 3.10-2.96 (1H, m),2.89-2.79 (1H, m), 2.75-2.66 (1H, m), 2.53-2.40 (1H, m), 2.16-2.02 (1H,m), 2.12 and 2.06 (3H, s), 1.96-1.84 (2H, m), 1.81-1.72 (1H, m),1.63-1.42 (3H, m), 1.39-1.25 (2H, m), 0.85 (3H, d), 0.79 and 0.78 (3H, 2× d), 0.72-0.64 (2H, m), 0.59-0.51 (2H, m) 171

543 8.90 and 8.65 (1H, 2 × d), 8.44 and 8.39 (1H, 2 × d), 7.88-7.82 (1H,dt), 7.74 and 7.69 (1H, 2 × d), 7.48 and 7.47 (1H, 2 × d), 7.37-7.21(5H, m), 6.73 (1H, d), 6.64 and 6.63 (1H, d), 5.10-5.02 (1H, m), 2.89-2.79 (1H, m), 2.64-2.19 (7H, m), 2.36- 2.20 (2H, br m), 2.17-2.03 (1H,m), 2.13 and 2.06 (3H, 2 × s), 1.98-1.90 (1H, m), 0.92 (6H, d), 0.81 and0.79 (3H, 2 × d), 0.72-0.64 (2H, m), 0.59-0.50 (2H, m) 172

501 9.32 and 9.19 (1H, 2 × d), 8.45 and 8.41 (1H, 2 × d), 7.86 (1H, dd),7.74 and 7.70 (1H, 2 × d), 7.49 and 7.48 (1H, 2 × d), 7.39-7.20 (5H, m),6.72 and 6.71 (1H, 2 × d), 6.62 (1H, d), 5.07 (1H, dd), 2.91- 2.69 (m,5H), 2.25-2.04 (3H, m), 2.11 and 2.05 (3H, 2 × s), 1.95-1.88 (1H, m),0.78 and 0.76 (3H, 2 × d), 0.72-0.64 (2H, m), 0.59-0.51 (2H, m) 173

506 8.89 and 8.72 (1H, 2 × d), 8.45 and 8.40 (1H, 2 × d), 7.86 (1H, dd),7.74 and 7.71 (1H, 2 × d), 7.49 and 7.48 (1H, 2 × d), 7.38-7.20 (5H, m),6.735 and 6.73 (1H, 2 × d), 6.63 (1H, d), 5.13-5.04 (1H, m), 2.90-2.79(1H, m), 2.75-2.50 (7H, m), 2.43-2.31 (2H, m), 2.27-2.04 (2H, m), 2.22(3H, s), 2.12 and 2.06 (3H, 2 × s), 1.84-1.71 (2H, m), 0.79 and 0.77(3H, 2 × d), 0.72-0.65 (2H, m), 0.59-0.51 (2H, m) 174

518 9.31 and 9.19 (1H, 2 × d), 8.45 and 8.40 (1H, 2 × d), 7.86 (1H, d),7.74 and 7.70 (1H, 2 × d), 7.49 and 7.48 (1H, 2 × d), 7.39-7.21 (5H, m),6.72 (1H, d), 6.63 (1H, d), 5.10-5.04 (1H, m), 4.71 (1H, d), 2.91-2.78(1H, m), 2.73-1.71 (11H, m), 2.11 and 2.05 (3H, s), 0.78 and 0.77 (3H, 2× d), 0.72-0.64 (2H, m), 0.59-0.51 (2H, m) 175

536 9.25 and 9.08 (1H, 2 × d), 8.45 and 8.40 (1H, 2 × d), 7.86 (1H, d),7.74 and 7.70 (1H, 2 × d), 7.49 and 7.48 (1H, 2 × d), 7.39-7.22 (5H, m),6.74 (1H, d), 6.64 (1H, d), 5.11-5.04 (1H, m), 2.89-2.79 (1H, m),2.76-1.95 (11H, m), 2.11 and 2.05 (3H, 2 × s), 0.79 and 0.78 (3H, 2 ×d), 0.73-0.64 (2H, m), 0.59-0.51 (2H, m) 176

543 9.21 and 9.01 (1H, d), 8.44 and 8.39 (1H, 2 × d), 7.88-7.82 (1H, m),7.74 and 7.69 (1H, 2 × d), 7.48 and 7.46 (1H, 2 × d), 7.38-7.20 (5H, m),6.72 (1H, d), 6.63 (1H, d), 5.10-5.02 (1H, m), 3.16-3.01 (1H, m),2.89-2.71 (m, 2H), 2.12, 2.10, 2.10 and 2.06 (9H, 4 × s), 2.19-1.49(10H, m), 0.78 and 0.77 (3H, 2 × d), 0.71- 0.64 (2H, m), 0.59-0.51 (2H,m) 177

568 8.95 and 8.67 (1H, 2 × d), 8.44 and 8.39 (1H, 2 × d), 7.85 (1H, dd),7.74 and 7.69 (1H, 2 × d), 7.48 and 7.47 (1H, 2 × d), 7.38-7.21 (5H, m),6.73 (1H, d), 6.64 (1H, d), 5.11-5.01 (1H, m), 3.23-3.08 (1H, m),2.89-2.78 (2H, m), 2.57-1.54 (10H, m), 2.12 and 2.06 (3H, 2 × s), 0.82and 0.79 (3H, 2 × d), 0.72-0.64 (2H, m), 0.59-0.50 (2H, m) 178

515 8.69 and 8.53 (1H, 2 × d), 8.46 and 8.40 (1H, 2 × d), 7.85 (1H, d),7.75-7.68 (2H, m), 7.48 and 7.47 (1H, 2 × d), 7.39-7.22 (5H, m), 6.75and 6.74 (1H, 2 × d), 6.65 and 6.64 (1H, 2 × d), 5.11-5.03 (1H, m),3.46-3.34 (1H, m), 3.21-3.10 (1H, m), 3.00-2.70 (4H, m), 2.44-2.29 (1H,m), 2.22-2.09 (1H, m), 2.11 and 2.04 (3H, 2 × s), 2.08-2.00 (1H, m),0.83 and 0.82 (3H, 2 × d), 0.72-0.64 (2H, m), 0.59- 0.51 (2H, m) 179

558 9.34 and 9.22 (1H, 2 × d), 8.45 and 8.41 (1H, 2 × d), 7.87 (1H, dd),7.73 and 7.70 (1H, 2 × d), 7.49 and 7.48 (1H, 2 × d), 7.38-7.21 (5H, m),6.715 and 6.713 (1H, 2 × d), 6.62 (1H, d), 5.07 (1H, dd), 3.82 (4H, d),2.89-2.78 (1H, m), 2.71-2.54 (1H, m), 2.42-2.25 (2H, m), 2.23-2.08 (1H,m), 2.11 and 2.05 (3H, 2 × s), 1.98- 1.91 (1H, m), 1.88-1.77 (3H, m),1.75- 1.64 (3H, m), 0.77 and 0.76 (3H, 2 × d), 0.72-0.64 (2H, m),0.59-0.51 (2H, m) 180

515 9.30 and 9.20 (1H, 2 × d), 8.45 and 8.41 (1H, 2 × d), 7.86 (1H, dd),7.74 and 7.69 (1H, 2 × d), 7.49 and 7.48 (1H, 2 × d), 7.38-7.20 (5H, m),6.715 and 6.711 (1H, 2 × d), 6.62 (1H, d), 5.10-5.02 (1H, m), 3.08-2.71(4H, m), 2.64-2.55 (1H, m), 2.19-2.08 (1H, m), 2.11 and 2.05 (3H, 2 ×s), 1.94-1.78 (4H, m), 1.46-1.36 (1H, m), 0.88 and 0.87 (3H, 2 × d),0.78 and 0.76 (3H, 2 × d), 0.72-0.64 (2H, m), 0.58- 0.51 (2H, m) 181

515 9.30 and 9.20 (1H, 2 × d), 8.45 and 8.41 (1H, 2 × d), 7.86 (1H, dd),7.74 and 7.69 (1H, 2 × d), 7.49 and 7.48 (1H, 2 × d), 7.38-7.20 (5H, m),6.715 and 6.711 (1H, 2 × d), 6.62 (1H, d), 5.10-5.02 (1H, m), 3.08-2.71(4H, m), 2.64-2.55 (1H, m), 2.19-2.08 (1H, m), 2.11 and 2.05 (3H, 2 ×s), 1.94-1.8 (3H, m), 1.46-1.36 (1H, m), 1.46-1.36 (1H, m), 0.88 and0.87 (3H, 2 × d), 0.78 and 0.76 (3H, 2 × d), 0.72-0.64 (2H, m),0.58-0.51 (2H, m) 182

488 8.61 and 8.52 (1H, 2 × d), 8.45 and 8.39 (1H, 2 × d), 7.86 (1H, dd),7.74 and 7.70 (1H, 2 × d), 7.49 and 7.47 (1H, 2 × d), 7.40-7.19 (5H, m),6.74 and 6.73 (1H, 2 × d), 6.63 and 6.62 (1H, 2 × d), 5.09-5.02 (1H, m),2.91-2.78 (1H, m), 2.35-2.13 (5H, m), 2.11 and 2.05 (3H, 2 × s), 1.81-1.59 (2H, m), 0.90-0.81 (9H, m), 0.73- 0.63 (2H, m), 0.59-0.50 (2H, m)183

472 8.46 and 8.39 (1H, 2 × d), 7.86 (1H, 2 × d), 7.75 and 7.70 (1H, 2 ×d), 7.49 and 7.48 (1H, 2 × d), 7.46-7.21 (5H, m), 6.78 and 6.77 (1H, 2 ×d), 6.68 and 6.67 (1H, 2 × d), 5.09-5.01 (1H, m), 2.90-2.79 (1H, m),2.67-2.57 (1H, m), 2.53-2.2 (3H, m), 2.13 and 2.06 (3H, 2 × s),0.99-0.89 (3H, m), 0.74-0.63 (2H, m), 0.61-0.41 (6H, m) 184

500 8.46-8.36 (m, 1H), 8.29-8.07 (m, 1H), 7.88-7.83 (m, 1H), 7.76-7.68(m, 1H), 7.50-7.45 (m, 1H), 7.41-7.35 (m, 2H), 7.34-7.30 (m, 2H),7.24-7.20 (m, 1H), 6.78-6.74 (m, 1H), 6.66-6.62 (m, 1H), 4.96-4.88 (m,1H), 2.94-2.88 (m, 1H), 2.87-2.79 (m, 1H), 2.40-2.20 (m, 3H), 2.08 (d,3H), 2.03-1.98 (m, 1H), 1.97- 1.91 (m, 1H), 1.90-1.78 (m, 1H), 1.68-1.55 (m, 2H), 1.34-1.25 (m, 1H), 0.95 (t, 3H), 0.92-0.89 (m, 3H),0.72-0.64 (m, 2H), 0.58-0.50 (m, 2H) 185

516 9.39-9.30 (m, 1H), 8.44 (dd, 1H), 7.87 (d, 1H), 7.72 (d, 1H), 7.49(t, 1H), 7.36- 7.31 (m, 2H), 7.29-7.22 (m, 3H), 6.74- 6.71 (m, 1H),6.64-6.61 (m, 1H), 5.08- 5.04 (m, 1H), 4.52 (t, 1H), 3.80-3.71 (m, 1H),3.08-2.91 (m, 1H), 2.88-2.80 (m, 1H), 2.55-2.45 (m, 2H), 2.21-2.13 (m,1H), 2.08 (d, 3H), 2.03-1.96 (m, 1H), 1.95-1.89 (m, 1H), 1.79-1.71 (m,1H), 1.71-1.63 (m, 2H), 1.63-1.54 (m, 1H), 1.15-1.05 (m, 1H), 0.79-0.74(m, 3H), 0.72-0.65 (m, 2H), 0.58-0.51 (m, 2H) 186

516 9.26 (dd, 1H), 8.47-8.39 (m, 1H), 7.87 (d, 1H), 7.72 (d, 1H),7.51-7.45 (m, 1H), 7.38-7.31 (m, 2H), 7.31-7.22 (m, 3H), 6.72 (d, 1H),6.62 (d, 1H), 5.08-5.02 (m, 1H), 3.70-3.59 (m, 1H), 2.99-2.91 (m, 1H),2.89-2.73 (m, 2H), 2.19-2.07 (m, 1H), 2.07 (d, 3H), 1.98-1.92 (m, 1H),1.85-1.63 (m, 4H), 1.61-1.49 (m, 1H), 1.10-0.97 (m, 1H), 0.80-0.73 (m,3H), 0.72-0.64 (m, 2H), 0.60-0.51 (m, 2H) 187

515 8.47-8.38 (m, 1H), 7.88-7.84 (m, 1H), 7.76-7.70 (m, 1H), 7.51-7.46(m, 1H), 7.36-7.28 (m, 4H), 7.27-7.20 (m, 1H), 6.75-6.72 (m, 1H),6.65-6.62 (m, 1H), 5.05-4.98 (m, 1H), 2.90-2.78 (m, 3H), 2.69-2.62 (m,1H), 2.47-2.31 (m, 4H), 2.27-2.16 (m, 2H), 2.06 (d, 3H), 1.96- 1.82 (m,1H), 0.92-0.87 (m, 3H), 0.86- 0.80 (m, 3H), 0.72-0.64 (m, 2H), 0.59-0.51 (m, 2H) 188

541 9.05-8.57 (m, 2H), 8.51-8.36 (m, 1H), 7.89-7.84 (m, 1H), 7.76-7.69(m, 1H), 7.66-7.20 (m, 7H), 7.11-6.94 (m, 1H), 6.86-6.72 (m, 2H),5.20-5.04 (m, 1H), 3.73 (s, 4H), 3.05-2.60 (m, 4H), 2.18- 2.04 (m, 5H),2.03-1.79 (m, 3H), 1.10- 0.97 (m, 2H), 0.75-0.63 (m, 2H), 0.59- 0.49 (m,2H) 189

518 δ (CD₃OD) 7.86-7.80 (m, 1H), 7.76- 7.67 (m, 1H), 7.52-7.36 (m, 5H),7.34- 7.28 (m, 1H), 6.94 (dd, 1H), 6.71 (dd, 1H), 5.34-5.26 (m, 1H),3.72-3.34 (m, 3H), 3.20-3.10 (m, 2H), 3.09-2.89 (m, 4H), 2.87-2.73 (m,2H), 2.19 (d, 3H), 1.08- 0.99 (m, 3H), 0.83-0.75 (m, 2H), 0.65- 0.55 (m,2H) 190

502 9.18 (m, 1H), 8.43 (m, 1H), 7.86 (dd, 1H), 7.72 (dd, 1H), 7.49 (d,1H), 7.37-7.28 (m, 4H), 7.27-7.22 (m, 1H), 6.74 (dd, 1H), 6.63 (dd, 1H),5.04 (m, 1H), 4.60- 4.55 (m, 1H), 4.27-4.18 (m, 1H), 2.90- 2.79 (m, 2H),2.69-2.59 (m, 1H), 2.48- 2.42 (m, 1H), 2.41-2.31 (m, 2H), 2.28- 2.21 (m,1H), 2.13-1.97 (m, 5H), 1.62- 1.53 (m, 1H), 0.78 (d, 3H), 0.72-0.64 (m,2H), 0.59-0.51 (m, 2H) 191

619 δ (CD₃OD) 7.87-7.81 (m, 1H), 7.72- 7.65 (m, 1H), 7.51-7.45 (m, 1H),7.34- 7.27 (m, 4H), 7.26-7.22 (m, 1H), 6.76- 6.73 (m, 1H), 6.54-6.51 (m,1H), 5.12- 5.07 (m, 1H), 3.26-3.11 (m, 2H), 3.07- 2.94 (m, 2H),2.87-2.60 (m, 7H), 2.59- 2.24 (m, 6H), 2.22-2.12 (m, 3H), 2.10- 1.96 (m,2H), 0.87-0.82 (m, 3H), 0.81- 0.74 (m, 2H), 0.64-0.57 (m, 2H) 192

543 8.78-8.56 (m, 1H), 8.45-8.36 (m, 1H), 7.84-7.80 (m, 1H), 7.71-7.65(m, 1H), 7.47-7.42 (m, 1H), 7.34-7.25 (m, 4H), 7.24-7.18 (m, 1H),7.11-7.07 (m, 1H), 6.72-6.70 (m, 1H), 6.64-6.58 (m, 2H), 5.06-5.01 (m,1H), 3.05-2.94 (m, 1H), 2.86-2.76 (m, 1H), 2.75-2.62 (m, 1H), 2.46-2.34(m, 1H), 2.11-1.96 (m, 5H), 1.94-1.84 (m, 2H), 1.83-1.73 (m, 2H),1.72-1.60 (m, 3H), 0.82-0.74 (m, 3H), 0.69-0.61 (m, 2H), 0.56-0.48 (m,2H) 193

504 9.09-8.94 (m, 1H), 8.45-8.36 (m, 1H), 7.86-7.82 (m, 1H), 7.72-7.68(m, 1H), 7.48-7.43 (m, 1H), 7.36-7.26 (m, 4H), 7.23-7.17 (m, 1H),6.71-6.68 (m, 1H), 6.60-6.57 (m, 1H), 5.07-5.01 (m, 1H), 4.53-4.41 (m,1H), 3.30-3.29 (m, 2H), 2.85-2.78 (m, 1H), 2.35-2.28 (m, 2H), 2.21-2.11(m, 1H), 2.09-2.02 (m, 3H), 0.91-0.89 (m, 3H), 0.89-0.87 (m, 3H),0.82-0.78 (m, 3H), 0.70-0.62 (m, 2H), 0.56-0.49 (m, 2H) 194

529 9.44-8.84 (m, 1H), 8.41 (d, 1H), 8.24- 8.13 (m, 1H), 7.86 (dd, 1H),7.72 (dd, 1H), 7.51-7.47 (m, 1H), 7.39-7.22 (m, 4H), 7.03 (d, 1H), 6.76(dd, 1H), 6.67 (d, 1H), 5.12-5.06 (m, 1H), 3.46-3.26 (m, 3H), 3.02-2.95(m, 1H), 2.89-2.79 (m, 1H), 2.35-2.22 (m, 1H), 2.14-1.98 (m, 4H),1.90-1.81 (m, 1H), 1.26-1.12 (m, 6H), 0.79-0.74 (m, 3H), 0.73-0.65 (m,2H), 0.58-0.51 (m, 2H) 195

515 δ (CD₃OD) 7.87-7.81 (m, 1H), 7.72 (d, J = 26.7 Hz, 1H), 7.52-7.46(m, 1H), 7.45- 7.34 (m, 4H), 7.31-7.26 (m, 1H), 6.94- 6.88 (m, 1H),6.69-6.64 (m, 1H), 5.32- 5.21 (m, 1H), 3.55-3.46 (m, 2H), 3.23- 2.99 (m,3H), 2.92-2.78 (m, 3H), 2.59- 2.44 (m, 1H), 2.31-2.13 (m, 5H), 1.91-1.75 (m, 2H), 1.04-0.96 (m, 3H), 0.83- 0.74 (m, 2H), 0.66-0.57 (m, 2H)196

527 9.61-9.15 (m, 1H), 8.46-8.39 (m, 1H), 7.84 (dd, 1H), 7.74-7.62 (m,1H), 7.48- 7.43 (m, 1H), 7.36-7.15 (m, 5H), 6.70- 6.67 (m, 1H),6.61-6.56 (m, 1H), 5.06- 4.86 (m, 1H), 3.19-3.16 (m, 1H), 3.09- 3.02 (m,1H), 2.90-2.56 (m, 5H), 2.45- 2.37 (m, 1H), 2.37-2.31 (m, 1H), 2.20-2.19 (m, 3H), 2.05 (d, J = 20.5 Hz, 3H), 1.82-1.67 (m, 1H), 1.60-1.51(m, 1H), 0.98-0.92 (m, 1H), 0.77-0.73 (m, 2H), 0.70-0.62 (m, 2H),0.57-0.49 (m, 2H) 197

514 9.06-8.52 (m, 1H), 8.46-8.33 (m, 1H), 7.86-7.81 (m, 1H), 7.72-7.63(m, 1H), 7.48-7.43 (m, 1H), 7.38-7.24 (m, 4H), 7.24-7.15 (m, 1H),6.71-6.64 (m, 1H), 6.62-6.56 (m, 1H), 5.15-4.50 (m, 1H), 2.87-2.77 (m,1H), 2.45-2.35 (m, 2H), 2.35-2.20 (m, 1H), 2.08-2.01 (m, 4H), 2.00-1.92(m, 1H), 1.74-1.57 (m, 3H), 1.56-1.46 (m, 1H), 1.03-0.62 (m, 11H),0.57-0.48 (m, 2H)

Example 198

N-Cyclopropyl-3-[3-[[1-[2-[2-(ethylamino)ethoxy]phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

a) 3,3-Dimethyl-2(3H)-benzofuranone

A solution of benzofuran-2(3H)-one (20 g) dissolved in DMF (250 mL) wastreated with iodomethane (33.4 mL) at 0° C. before adding potassiumcarbonate (134 g) portionwise over a period of 10 minutes undernitrogen. The resulting suspension was stirred at 25° C. for 3 days. Themixture was filtered and the solids washed with ethyl acetate. Thefiltrate was diluted with 2M hydrochloric acid, extracted with ethylacetate. The organic was dried (MgSO₄), filtered and evaporated toafford crude product. The crude product was purified (SiO2chromatography eluting with 30% dichloromethane in iso-hexane). Purefractions were evaporated to dryness to afford the subtitle compound(19.70 g).

¹H NMR δ (CDCl₃) 7.32-7.08 (m, 4H), 1.53 (s, 6H).

b) 2-Hydroxy-α,α-dimethyl-benzeneacetamide

3,3-Dimethylbenzofuran-2(3H)-one (Example 198a, 19.7 g) was dissolved in7N ammonia in methanol (50 mL) under nitrogen. The resulting solutionwas stirred at 25° C. for 16 h. The reaction mixture was evaporated toafford crude product. The solid was triturated with diethyl ether andfiltered to give the subtitle compound (15.34 g).

¹H NMR δ (DMSO-d₆) 7.18 (d, 1H), 7.07-7.00 (m, 1H), 6.78-6.71 (m, 2H),6.63 (s, 1H), 6.38 (s, 1H), 3.35 (s, 1H), 1.43 (s, 6H).

c) α,α-Dimethyl-2-(phenylmethoxy)-benzeneacetamide

A solution of 2-hydroxy-α,α-dimethyl-benzeneacetamide (Example 198b,15.34 g) dissolved in DMF (150 mL) was treated with potassium carbonate(11.83 g) and benzyl bromide (10.18 mL) under nitrogen. The resultingmixture was stirred at 25° C. for 16 h. The reaction mixture was dilutedwith water (500 mL) and stirred for 30 min. The solid was filtered offand washed with water and dried in vacuo to afford the subtitle compound(19.45 g).

MS: APCI(+ve) 270 (M+H)⁺

d) α,α-Dimethyl-2-(phenylmethoxy)-benzenemethanamine

A solution of α,α-dimethyl-2-(phenylmethoxy)-benzeneacetamide (Example198c, 19.45 g) dissolved in acetonitrile (200 mL) and water (200 mL) wastreated with (Bis(trifluoroacetoxy)iodo)benzene (31.1 g) under nitrogen.The resulting solution was stirred at 20° C. for 60 h. The reactionmixture was diluted with water (300 mL), and extracted with diethylether. The aqueous layer was basified at 0° C. with 2M NaOH solution andextracted with ethyl acetate. The organic was dried (MgSO₄), filteredand evaporated to afford the subtitle compound (13.26 g).

¹H NMR δ (DMSO-d₆) 7.54-7.29 (m, 6H), 7.22-7.13 (m, 1H), 7.07 (d, 1H),6.93-6.84 (m, 1H), 5.20 (s, 2H), 2.21 (s, 2H), 1.46 (s, 6H).

e)3-[3-[[1-[2-(2-Chloroethoxy)phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide

The subtitle compound was prepared by usingα,α-dimethyl-2-(phenylmethoxy)-benzenemethanamine (Example 198d) usingthe methods described in example 134 to giveN-cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(1-pyrrolidinyl)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamidewhich was alkylated with 1-bromo-2-chloroethane as described in example167e to afford the subtitle product.

MS: APCI(+ve) 481 (M+H)⁺.

f)N-Cyclopropyl-3-[3-[[1-[2-[2-(ethylamino)ethoxy]phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

The title compound was prepared from3-[3-[[1-[2-(2-chloroethoxy)phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide(Example 198e) and 70% ethylamine in water using the method of example167f.

MS: APCI(+ve) 490 (M+H)⁺.

¹H NMR δ (DMSO-d₆) 8.42 (d, 1H), 7.85 (d, 1H), 7.74 (s, 1H), 7.47 (d,1H), 7.34 (d, 1H), 7.23-7.14 (m, 1H), 6.99-6.87 (m, 3H), 6.69-6.59 (m,2H), 4.01-3.89 (m, 2H), 2.90-2.78 (m, 3H), 2.54-2.44 (m, 2H), 2.06 (s,3H), 1.80 (s, 6H), 0.92-0.78 (m, 3H), 0.73-0.64 (m, 2H), 0.59-0.50 (m,2H).

The following examples 199-213 (Table 6) were prepared in a similarmanner to Example 198.

Example 199

N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(1-piperazinyl)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 200

N-Cyclopropyl-3-[3-[[1-[2-[2-(diethylamino)ethoxy]phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 201

N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(1-piperidinyl)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 202

N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(4-methyl-1-piperazinyl)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 203

N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(4-morpholinyl)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 204

N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[4-(methylamino)butoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 205

N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[4-[(2,2,2-trifluoroethyl)amino]butoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 206

N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[4-(4-methyl-1-piperazinyl)butoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 207

N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[3-[(2,2,2-trifluoroethyl)amino]propoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 208

N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[3-(4-methyl-1-piperazinyl)propoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 209

N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[1-methyl-2-(4-methyl-1-piperazinyl)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 210

N-Cyclopropyl-3-[3-[[1-[2-[2-[(2-methoxyethyl)amino]ethoxy]phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 211

N-Cyclopropyl-3-[3-[[1-[2-[2-[(2-hydroxyethyl)amino]ethoxy]phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 212

N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-[(1-methylethyl)amino]ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 213

N-Cyclopropyl-3-[3-[[1-[2-[2-[[(2S)-2-hydroxypropyl]amino]ethoxy]phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-6-benzamide

TABLE 6

MS [M + H]⁺ Example R m/z ¹H NMR δ (DMSO-d₆) 199

531 8.43 (d, 1H), 7.85 (d, 1H), 7.75 (s, 1H), 7.47 (d, 1H), 7.32 (d,1H), 7.22-7.14 (m, 1H), 6.99-6.83 (m, 3H), 6.68-6.58 (m, 2H), 4.06-3.91(m, 2H), 2.90-2.78 (m, 1H), 2.69-2.58 (m, 6H), 2.39-2.28 (m, 4H), 2.11(s, 3H), 1.87 (s, 6H), 0.73- 0.63 (m, 2H), 0.60-0.50 (m, 2H) 200

517 8.47-8.38 (m, 1H), 7.91-7.81 (m, 1H), 7.77 (s, 1H), 7.45 (d, 1H),7.32 (d, 1H), 7.23-7.13 (m, 1H), 7.02-6.92 (m, 1H), 6.93-6.83 (m, 2H),6.68-6.58 (m, 2H), 3.98-3.85 (m, 2H), 2.86-2.70 (m, 3H), 2.53-2.46 (m,4H), 2.11 (s, 3H), 1.87 (s, 6H), 0.92 (t, 6H), 0.72-0.65 (m, 2H),0.59-0.52 (m, 2H) 201

530 8.43 (d, 1H), 7.86 (d, 1H), 7.77 (s, 1H), 7.48 (d, 1H), 7.32 (d,1H), 7.22-7.14 (m, 1H), 7.00-6.84 (m, 3H), 6.68-6.57 (m, 2H), 4.06-3.90(m, 2H), 2.89-2.78 (m, 1H), 2.70-2.58 (m, 2H), 2.44-2.32 (m, 4H), 2.02(s, 3H), 1.79 (s, 6H), 1.52- 1.28 (m, 6H), 0.74-0.64 (m, 2H), 0.60- 0.51(m, 2H) 202

545 8.44-8.36 (m, 1H), 7.84 (d, 1H), 7.73 (s, 1H), 7.46 (d, 1H), 7.30(d, 1H), 7.19- 7.12 (m, 1H), 6.97-6.84 (m, 3H), 6.67- 6.56 (m, 2H),4.00-3.89 (m, 2H), 2.87- 2.76 (m, 1H), 2.69-2.58 (m, 2H), 2.45- 2.17 (m,8H), 2.13-2.03 (m, 6H), 1.76 (s, 6H), 0.68-0.62 (m, 2H), 0.56-0.49 (m,2H) 203

532 8.44 (d, 1H), 7.88 (d, 1H), 7.76 (s, 1H), 7.50 (d, 1H), 7.34 (d,1H), 7.23-7.17 (m, 1H), 7.01-6.85 (m, 3H), 6.69-6.60 (m, 2H), 4.06-3.97(m, 2H), 3.58-3.49 (m, 4H), 2.90-2.81 (m, 1H), 2.72-2.63 (m, 2H),2.47-2.40 (m, 4H), 2.13 (s, 3H), 1.88 (s, 6H), 0.73-0.66 (m, 2H),0.60-0.53 (m, 2H) 204

504 8.53-8.44 (m, 1H), 7.89 (d, 1H), 7.78 (s, 1H), 7.53 (d, 1H), 7.35(d, 1H), 7.20 (t, 1H), 7.01-6.86 (m, 3H), 6.74-6.59 (m, 2H), 4.01-3.86(m, 2H), 2.94-2.81 (m, 1H), 2.50-2.43 (m, 2H), 2.26 (s, 3H), 2.15 (s,3H), 1.91 (s, 6H), 1.80- 1.70 (m, 2H), 1.61-1.51 (m, 2H), 0.75- 0.65 (m,2H), 0.61-0.51 (m, 2H) 205

572 8.48-8.39 (m, 1H), 7.87 (d, 1H), 7.76 (s, 1H), 7.48 (d, 1H), 7.31(d, 1H), 7.23- 7.11 (m, 2H), 6.99-6.85 (m, 3H), 6.71- 6.57 (m, 2H),4.00-3.86 (m, 2H), 3.27- 3.14 (m, 2H), 2.90-2.77 (m, 1H), 2.69- 2.56 (m,2H), 2.01 (s, 3H), 1.78 (s, 6H), 1.78-1.68 (m, 2H), 1.61-1.51 (m, 2H),0.74-0.64 (m, 2H), 0.58-0.48 (m, 2H) 206

573 8.50-8.42 (m, 1H), 7.89 (d, 1H), 7.79 (s, 1H), 7.55-7.46 (m, 1H),7.34 (d, 1H), 7.25-7.17 (m, 1H), 7.02-6.87 (m, 3H), 6.75-6.60 (m, 2H),4.03-3.88 (m, 2H), 2.94-2.79 (m, 1H), 2.36-2.21 (m, 10H), 2.17-2.09 (m,6H), 1.89-1.82 (m, 6H), 1.79-1.72 (m, 2H), 1.62-1.52 (m, 2H), 0.75-0.65(m, 2H), 0.62-0.53 (m, 2H) 207

558 8.48-8.38 (m, 1H), 7.86 (d, 1H), 7.78 (s, 1H), 7.48 (d, 1H), 7.32(d, 1H), 7.23- 7.12 (m, 1H), 6.97-6.87 (m, 3H), 6.71- 6.60 (m, 2H),4.02-3.91 (m, 2H), 3.20- 3.10 (m, 2H), 2.89-2.70 (m, 3H), 2.39- 2.29 (m,1H), 2.13 (s, 3H), 1.79 (s, 7H), 0.74-0.63 (m, 2H), 0.58-0.47 (m, 2H)208

559 8.44-8.37 (m, 1H), 7.85 (d, 1H), 7.76 (s, 1H), 7.48 (d, 1H), 7.34(d, 1H), 7.23- 7.16 (m, 1H), 6.99-6.85 (m, 3H), 6.73- 6.59 (m, 2H),4.02-3.85 (m, 2H), 2.92- 2.78 (m, 1H), 2.45-2.16 (m, 10H), 2.15- 2.05(m, 6H), 1.91-1.81 (m, 8H), 0.73- 0.63 (m, 2H), 0.58-0.48 (m, 2H) 209

559 8.45-8.40 (m, 1H), 7.86 (dd, 1H), 7.71- 7.67 (m, 1H), 7.50-7.47 (m,1H), 7.34- 7.31 (m, 1H), 7.16-7.16 (m, 1H), 6.99 (s, 1H), 6.87-6.85 (m,2H), 6.64 (ddd, 2H), 4.67-4.63 (m, 1H), 2.84 (d, 2H), 2.36-2.25 (m, 6H),2.11 (t, 6H), 2.08 (s, 2H), 1.86 (d, 3H), 1.79 (d, 3H), 1.12 (dd, 3H),0.69 (dd, 2H), 0.56-0.54 (m, 2H) 210

520 8.47 (s, 1H), 7.89 (d, 1H), 7.80 (s, 1H), 7.48 (d, 1H), 7.34 (d,1H), 7.23-7.14 (m, 1H), 6.98-6.87 (m, 3H), 6.65 (d, 2H), 4.04-3.89 (m,2H), 3.34-3.26 (m, 2H), 3.19 (s, 3H), 2.92-2.82 (m, 3H), 2.71-2.60 (m,2H), 2.15 (s, 3H), 1.89 (s, 6H), 0.74-0.63 (m, 2H), 0.60-0.49 (m, 2H)211

506 8.45-8.39 (m, 1H), 7.86 (d, 1H), 7.75 (s, 1H), 7.48 (d, 1H), 7.31(d, 1H), 7.22- 7.16 (m, 1H), 6.99-6.85 (m, 3H), 6.69- 6.59 (m, 2H),4.40-4.29 (m, 1H), 4.01- 3.90 (m, 2H), 3.45-3.35 (m, 2H), 2.93- 2.83 (m,3H), 2.65-2.54 (m, 2H), 2.13 (s, 3H), 1.83 (d, 6H), 0.74-0.63 (m, 2H),0.61-0.50 (m, 2H) 212

504 8.44-8.40 (m, 1H), 7.85 (d, 1H), 7.74 (s, 1H), 7.47 (d, 1H), 7.34(d, 1H), 7.22- 7.17 (m, 1H), 6.99-6.87 (m, 3H), 6.69- 6.60 (m, 2H),4.02-3.89 (m, 2H), 2.90- 2.80 (m, 3H), 2.73-2.65 (m, 1H), 2.12 (s, 3H),1.87-1.80 (m, 6H), 0.89 (d, 6H), 0.72-0.66 (m, 2H), 0.57-0.52 (m, 2H)213

520 8.48 (s, 1H), 7.87 (d, 1H), 7.79 (s, 1H), 7.48 (d, 1H), 7.34 (d,1H), 7.24-7.14 (m, 1H), 7.00-6.85 (m, 3H), 6.64 (d, 2H), 4.40-4.26 (m,1H), 4.03-3.89 (m, 2H), 3.67-3.53 (m, 1H), 2.95-2.81 (m, 3H), 2.47-2.39(m, 2H), 2.12 (s, 3H), 1.87 (s, 6H), 0.97 (d, 3H), 0.73-0.64 (m, 2H),0.59-0.51 (m, 2H)

Example 214

N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-(4-piperidinylmethoxy)phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

N-Cyclopropyl-3-(3-(2-(2-hydroxyphenyl)propan-2-ylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzamide(Example 134, 0.172 g), potassium carbonate (0.114g) and tert-butyl4-(bromomethyl)piperidine-1-carboxylate (0.114 g) were stirred togetherin acetonitrile (10 mL) at reflux overnight. The cooled reaction mixturewas evaporated to dryness and the residue partitioned between ethylacetate (20 mL) and water (20 mL). The separated aqueous layer wasfurther extracted into ethyl acetate (2×20 mL), the combined organicswere dried (MgSO₄) and evaporated. The residue was dissolved indichloromethane (10 mL) and treated with trifluoroacetic acid (1 ml),after stirring at room temperature for 1 h, the solvent was evaporatedto leave the crude product. Purification by preparative HPLC (Geminicolumn —acetonitrile/0.2% ammonia mobile phase) afforded the titlecompound as a solid (50 mg).

MS: APCI(+ve) 516 (M+H)⁺.

¹H NMR δ (DMSO-d₆) 8.44 (s, 1H), 7.86 (d, 1H), 7.72 (s, 1H), 7.49 (d,1H), 7.32 (d, 1H), 7.19 (t, 1H), 6.96 (d, 1H), 6.89 (t, 1H), 6.81 (s,1H), 6.64 (q, 2H), 3.80-3.69 (m, 2H), 2.95-2.78 (m, 2H), 2.46-2.33 (m,2H), 2.10 (s, 3H), 1.83 (s, 6H), 1.74-1.62 (m, 2H), 1.25-1.01 (m, 4H),0.76-0.45 (m, 4H).

The following examples 215-219 (Table 7) were prepared in a similarmanner to Example 214.

Example 215

N-Cyclopropyl-4-methyl-3-[3-[[1-[2-(3-azetidinyloxy)phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 216

N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-(3-pyrrolidinyloxy)phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 217

N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(4-piperidinyl)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 218

N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-(3-piperidinylmethoxy)phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 219

N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-(4-piperidinyloxy)phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

TABLE 7

MS [M + H]⁺ Example R m/z ¹H NMR δ (DMSO-d₆) 215

474 8.49-8.41 (m, 1H), 7.87 (d, 1H), 7.76 (s, 1H), 7.48 (d, 1H), 7.34(d, 1H), 7.18- 7.12 (m, 1H), 6.93-6.87 (m, 2H), 6.67- 6.61 (m, 3H),4.95-4.89 (m, 1H), 3.73- 3.64 (m, 2H), 3.50-3.36 (m, 3H), 2.88- 2.79 (m,1H), 2.14 (s, 3H), 1.88 (s, 6H), 0.73-0.64 (m, 2H), 0.59-0.50 (m, 2H)216

488 8.55-8.42 (m, 1H), 7.93-7.80 (m, 1H), 7.69 (d, 1H), 7.48 (d, 1H),7.35 (d, 1H), 7.22-7.13 (m, 1H), 6.93-6.85 (m, 3H), 6.68-6.60 (m, 2H),4.89-4.80 (m, 1H), 3.03-2.59 (m, 4H), 2.05 (s, 3H), 2.05- 1.92 (m, 1H),1.87-1.57 (m, 8H), 0.74- 0.64 (m, 2H), 0.58-0.48 (m, 2H) 217

530 8.49-8.42 (m, 1H), 7.89-7.82 (m, 1H), 7.71 (s, 1H), 7.48-7.42 (m,1H), 7.31 (d, 1H), 7.20-7.14 (m, 1H), 6.96 (d, 1H), 6.89-6.83 (m, 2H),6.67-6.56 (m, 2H), 3.98-3.87 (m, 2H), 2.88-2.77 (m, 3H), 2.37-2.27 (m,2H), 2.10 (s, 3H), 1.84 (s, 6H), 1.65-1.47 (m, 6H), 1.05- 0.88 (m, 2H),0.70-0.61 (m, 2H), 0.57- 0.48 (m, 2H) 218

516 8.48-8.40 (m, 1H), 7.87 (d, 1H), 7.76 (s, 1H), 7.49 (d, 1H), 7.31(d, 1H), 7.22- 7.14 (m, 1H), 7.02-6.94 (m, 1H), 6.92- 6.80 (m, 2H),6.71-6.59 (m, 2H), 3.85- 3.69 (m, 2H), 3.05-2.99 (m, 1H), 2.89- 2.73 (m,2H), 2.44-2.27 (m, 4H), 2.13 (s, 3H), 1.92-1.85 (m, 1H), 1.86 (s, 6H),1.56-1.50 (m, 1H), 1.37-1.14 (m, 2H), 0.72-0.65 (m, 2H), 0.58-0.51 (m,2H) 219

502 8.46-8.41 (m, 1H), 7.86 (d, 1H), 7.73 (s, 1H), 7.49 (d, 1H), 7.34(d, 1H), 7.18- 7.12 (m, 1H), 6.97 (d, 1H), 6.88-6.83 (m, 2H), 6.69-6.60(m, 2H), 4.48-4.40 (m, 1H), 2.94-2.80 (m, 3H), 2.59-2.52 (m, 2H), 2.12(s, 3H), 1.87 (s, 8H), 1.50- 1.38 (m, 2H), 0.72-0.65 (m, 2H), 0.58- 0.51(m, 2H)

Example 220

N-Ethyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

a)3-[5-Bromo-3-[[1-methyl-1-[2-(phenylmethoxy)phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoicacid methyl ester

A solution of α,α-dimethyl-2-(phenylmethoxy)-benzenemethanamine (Example198d, 1.5 g) dissolved in dioxane (52.2 mL) was treated with methyl3-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-4-methylbenzoate (Example 1b,2.499 g) and N-ethyldiisopropylamine (1.083 mL) under nitrogen. Theresulting solution was stirred at 100° C. for 10 h. After cooling toroom temperature, the reaction mixture was diluted with water (50 mL),and extracted with ethyl acetate (100 mL×2). The organic was dried(MgSO₄), filtered and evaporated. The crude product was triturated with50% diethyl ether in iso-hexane for 3 h. The solid was filtered off toafford the subtitle compound (2.405 g).

MS: APCI(+ve) 563 (M+H)⁺.

b)3-[3-[[1-(2-Hydroxyphenyl)-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoicacid methyl ester

To3-[5-bromo-3-[[1-methyl-1-[2-(phenylmethoxy)phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoicacid, methyl ester (Example 220a, 2 g) in ethanol (50 mL) was addedammonium formate (3.14 g) and 10% Pd/C (0.378 g) and the reaction heatedat 75° C. for 1 h. The reaction was filtered through celite and thefiltrate concentrated in vacuo. The reaction mixture was diluted withwater (250 mL) and extracted with dichloromethane (250 mL). The organiclayer was dried (MgSO₄), filtered and concentrated in vacuo to give thesubtitle compound (1.410 g).

MS: APCI(+ve) 394 (M+H)⁺.

c)4-Methyl-3-[3-[[1-methyl-1-[2-[2-[methyl[(phenylmethoxy)carbonyl]amino]ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzoicacid methyl ester

To3-[3-[[1-(2-Hydroxyphenyl)-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoicacid methyl ester (Example 220b, 2.495 g) in acetonitrile (150 mL) wasadded potassium carbonate (1.753 g) followed by benzyl2-chloroethyl(methyl)carbamate (J. Med. Chem., 1992, 35 (17), 3246,1.660 g) and the reaction heated at 85° C. for 72 h under nitrogen.Further benzyl 2-chloroethyl(methyl)carbamate (0.58 g) and potassiumcarbonate (0.35 g) were added and the reaction stirred for 2 days. Thereaction mixture was cooled, evaporated to dryness and the residuepartitioned between water and dichloromethane and the organic layerseparated. The aqueous was further extracted with dichloromethane (2x)and the combined organics dried (Na₂SO₄) and evaporated. Purification(SiO₂ chromatography eluting with 40-100% ethyl acetate) gave thesubtitle product (1.97 g).

¹H NMR δ (DMSO-d₆) 7.96 (d, 1H), 7.82 (s, 1H), 7.56 (d, 1H), 7.32 (s,5H), 7.20-7.16 (m, 1H), 6.91 (t, 3H), 6.65 (d, 2H), 5.05 (s, 2H),4.09-3.99 (m, 3H), 3.84 (s, 2H), 2.92 (d, 3H), 2.13 (s, 3H), 1.99 (d,2H), 1.80 (s, 6H)

d)4-Methyl-3-[3-[[1-methyl-1-[2-[2-[methyl[(phenylmethoxy)carbonyl]amino]ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzoicacid

To4-Methyl-3-[3-[[1-methyl-1-[2-[2-[methyl[(phenylmethoxy)carbonyl]amino]ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzoicacid methyl ester (Example 220c, 1.97 g) in THF (11 mL) was addedlithium hydroxide monohydrate (0.424 g) in water (5.5 mL) (sonicatedsuspension) and the reaction stirred for 16 h at room temperature. Waterwas added and the solution acidified with 2M hydrochloric acid and thenextracted with ethyl acetate. The organic layer was dried (MgSO₄) andevaporated. Trituration with diethyl ether/iso-hexane afforded thesubtitle compound (1.790 g).

MS: APCI(+ve) 571 (M+H)+.

¹H NMR δ (DMSO-d₆) 7.95 (d, 1H), 7.79 (s, 1H), 7.54 (d, 1H), 7.32 (s,6H), 7.19 (d, 1H), 7.00-6.89 (m, 3H), 6.66 (s, 2H), 5.05 (s, 2H), 4.06(d, 2H), 3.64 (s, 2H), 2.92 (d, 3H), 2.12 (s, 3H), 1.80 (s, 6H).

e)[2-[2-[1-[[4-[5-[(Ethylamino)carbonyl]-2-methylphenyl]-3,4-dihydro-3-oxopyrazinyl]amino]-1-methylethyl]phenoxy]ethyl]methyl-carbamicacid phenylmethyl ester

To4-methyl-3-[3-[[1-methyl-1-[2-[2-[methyl[(phenylmethoxy)carbonyl]amino]ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzoicacid (Example 220d, 0.14g) in DMF (3 mL) were added0-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(0.158 g) followed by N-ethyldiisopropylamine (0.212 mL) and thereaction stirred for 15 min before ethylamine (0.032 mL) was added andthe reaction stirred for 3 h. The reaction was diluted with water andthe aqueous layer extracted with ethyl acetate. The combined organicswere dried (Na₂SO₄) and solvents removed in vacuo to give the subtitleproduct (1.10 g).

MS: APCI(+ve) 598 (M+H)⁺.

f)N-Ethyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

To[2-[2-[1-[[4-[5-[(ethylamino)carbonyl]-2-methylphenyl]-3,4-dihydro-3-oxopyrazinyl]amino]-1-methylethyl]phenoxy]ethyl]methyl-carbamicacid phenylmethyl ester (Example 220d, 1.10 g) was added ethanol (10 mL)and this was pumped through a Pd/C cartridge at 1 mL/min under max H₂ at50° C. on an H-Cube hydrogenator. The solvents were removed in vacuo andthe residue then taken up in acetonitrile. Purification by preparativeHPLC (ACE column, 0.2% TFA: acetonitrile eluent) followed by treatmentwith SCX resin (eluting with methanol (discarded) followed by 7N NH₃ inmethanol and collected the basic fractions) and trituration with diethylether afforded the title product (2 mg).

MS: APCI(+ve) 464 (M+H)⁺.

¹H NMR δ (DMSO-d₆) 8.49 (s, 1H), 7.88 (d, 1H), 7.76 (s, 1H), 7.49 (d,1H), 7.36 (d, 1H), 7.20 (t, 1H), 6.95 (m, 3H), 6.67 (d, 1H), 6.63 (d,1H), 4.05-3.98 (m, 2H), 3.28 (t, 2H), 2.96 (d, 2H), 2.33 (s, 3H), 2.10(s, 3H), 1.85 (s, 3H), 1.82 (s, 3H), 1.11 (t, 3H)

The following examples 221-229 (Table 8) were prepared in a similarmanner to Example 220:

Example 221

1-[4-Methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]benzoyl]-azetidine

Example 222

N-Ethoxy-4-methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 223

4-Methyl-N-(1-methylethyl)-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 224

N-Cyclobutyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 225

N-(2-Fluoroethyl)-4-methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 226

4-Methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-(2-methylpropyl)-benzamide

Example 227

4-Methyl-N-(1-methylcyclopropyl)-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 228

N-(2-Hydroxyethyl)-4-methyl-3-[3-O-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 229

4-Methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

TABLE 8

MS [M + Ex- H]⁺ ample R m/z ¹H NMR δ (DMSO-d₆) 221

476 7.64 (d, 1H), 7.48 (d, 2H), 7.35 (d, 1H), 7.19 (t, 1H), 6.98-6.88(m, 3H), 6.62 (ddd, 2H), 4.33 (d, 2H), 4.06-3.93 (m, 3H), 3.44 (q, 2H),2.83 (t, 2H), 2.27-2.25 (m, 3H), 2.11-2.06 (m, 3H), 1.83 (s, 6H), 1.06(td, 2H) 222

480 7.78 (d, 1H), 7.71 (s, 1H), 7.52 (d, 1H), 7.42 (d, 1H), 7.26 (m,1H), 7.24 (t, 1H), 7.01-6.96 (m, 2H), 6.70 (d, 1H), 6.63 (d, 1H), 4.26-4.09 (m, 2H), 3.92 (q, 2H), 3.40- 3.23 (m, 2H), 2.52 (s, 3H), 2.11 (s,3H), 1.89 (s, 3H), 1.80 (s, 3H), 1.21 (t, 3H) 223

478 8.23 (d, 1H), 7.89 (dd, 1H), 7.81 (d, 1H), 7.49 (d, 1H), 7.38 (dd,1H), 7.22 (dd, 1H), 7.12 (s, 1H), 7.00- 6.93 (m, 3H), 6.67 (dd, 2H),4.15- 4.06 (m, 2H), 2.44 (s, 3H), 2.44 (s, 2H), 2.11 (s, 3H), 1.84 (d,6H), 1.15 (d, 6H) 224

490 8.64 (d, 1H), 7.90 (dd, 1H), 7.82 (s, 1H), 7.49 (d, 1H), 7.40 (dd,1H), 7.23 (dd, 2H), 6.98 (q, 2H), 6.67 (dd, 2H), 4.41 (d, 1H), 4.21-4.15(m, 2H), 3.40-3.26 (m, 2H), 2.53 (s, 3H), 2.21 (m, 2H), 2.11 (s, 3H),2.05 (t, 2H), 1.88 (s, 6H), 1.72-1.61 (m, 2H) 225

482 8.73 (s, 1H), 7.92-7.82 (m, 2H), 7.53-7.37 (m, 2H), 7.17 (d, 2H),6.97 (s, 2H), 6.66 (s, 2H), 4.61 (s, 1H), 4.45 (s, 1H), 4.10 (s, 2H),3.56 (d, 2H), 3.17 (s, 2H), 2.44 (s, 3H), 2.12 (s, 3H), 1.84 (d, 6H) 226

492 8.47 (s, 1H), 7.90-7.87 (m, 1H), 7.75 (s, 1H), 7.49 (d, 1H), 7.34(d, 1H), 7.19 (m, 1H), 6.98-6.91 (m, 3H), 6.68-6.63 (m, 2H), 4.09-3.91(m, 1H), 3.18 (s, 2H), 3.16 (s, 2H), 2.84-2.82 (m, 2H), 2.09 (d, 3H),1.99 (s, 3H), 1.83 (s, 6H), 1.20- 1.09 (m, 6H) 227

490 8.66 (s, 1H), 7.85 (dd, 1H), 7.71 (s, 1H), 7.47 (d, 1H), 7.34 (dd,1H), 7.22-7.16 (m, 1H), 6.98-6.87 (m, 3H), 6.64 (dd, 2H), 3.96 (dtd,2H), 2.83 (t, 2H), 2.26 (s, 3H), 2.09 (s, 3H), 1.83 (s, 6H), 1.35 (s,3H), 0.73-0.70 (m, 2H), 0.61-0.57 (m, 2H) 228

480 8.47 (s, 1H), 7.92 (s, 1H), 7.76 (s, 1H), 7.54 (s, 1H), 7.33 (s,1H), 7.19 (s, 1H), 6.90 (s, 3H), 6.64 (s, 2H), 3.96 (s, 2H), 3.49 (s,2H), 3.31-3.31 (m, 2H), 2.83 (s, 2H), 2.26 (s, 3H), 2.10 (s, 3H), 1.83(s, 6H) 229

436 7.98 (s, 1H), 7.90 (dd, 1H), 7.76 (d, 1H), 7.49 (d, 1H), 7.41 (s,1H), 7.34 (dd, 1H), 7.19 (t, 1H), 6.96 (d, 1H), 6.90 (t, 2H), 6.65 (q,2H), 3.96 (ddd, 2H), 2.83 (t, 2H), 2.26 (s, 3H), 2.10 (s, 3H), 1.83 (d,6H)

Example 230

N-Cyclopropyl-3-[3-[[1-[2-[2-[[(2S)-2-hydroxypropyl]amino]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

3-(3-(1-(2-(2-Chloroethoxy)phenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-4-methylbenzamide(Example 167e, 100 mg) and (S)-(+)-1-amino-2-propanol (0.247 mL) werestirred together in dioxane (3 mL) in a sealed tube at 100° C. for 24 h.Purification of the cooled solution by preparative HPLC (Xbridgecolumn-acetonitrile/0.2% ammonia mobile phase) afforded the titlecompound (60 mg).

MS: APCI(+ve) 518 (M+H)⁺.

¹H NMR δ (DMSO-d₆) 8.36 (d, 1H), 7.85 (d, 1H), 7.68 (s, 1H), 7.53-7.43(m, 2H), 7.39-7.35 (m, 1H), 7.20 (t, 1H), 6.96 (d, 1H), 6.90-6.81 (m,2H), 6.70 (d, 1H), 4.41 (s, 1H), 4.06 (t, 2H), 3.69 (s, 1H), 2.96 (t,2H), 2.89-2.75 (m, 1H), 2.55-2.52 (m, 2H), 2.06 (s, 3H), 1.24-1.12 (m,4H), 1.02 (d, 3H), 0.71-0.62 (m, 2H), 0.56-0.48 (m, 2H).

The following examples 231-249 (Table 9) were prepared in a similarmanner to Example 230:

Example 231

N-Cyclopropyl-3-[3-[[1-[2-[2-[(2-methoxyethyl)amino]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 232

N-Cyclopropyl-3-[3-[[1-[2-[2-[4-(2-hydroxyethyl)-1-piperazinyl]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 233

N-Cyclopropyl-3-[3-[[1-[2-[2-[(2-hydroxyethyl)amino]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 234

N-Cyclopropyl-4-methyl-3-[3-[[1-[2-[2-[(1-methylethyl)amino]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 235

N-Cyclopropyl-3-[3-[[1-[2-[2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 236

N-Cyclopropyl-3-[3-[[1-[2-[2-[(3R)-3-hydroxy-1-pyrrolidinyl]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 237

N-Cyclopropyl-3-[3-[[1-[2-[2-(dimethylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 238

N-Cyclopropyl-4-methyl-3-[2-oxo-3-[0-[2-[2-(1-pyrrolidinyl)ethoxy]phenyl]cyclopropyl]amino]-1(2H)-pyrazinyl]-benzamide

Example 239

N-Cyclopropyl-3-[3-[[1-[2-[2-[(2S)-2-(hydroxymethyl)-1-pyrrolidinyl]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 240

N-Cyclopropyl-4-methyl-3-[2-oxo-3-[[1-[2-[2-[(2,2,2-trifluoroethyl)amino]ethoxy]phenyl]cyclopropyl]amino]-1(2H)-pyrazinyl]-benzamide

Example 241

N-Cyclopropyl-3-[3-[[1-[2-[2-(ethylmethylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 242

N-Cyclopropyl-3-[3-[[1-[2-[2-[(3-hydroxy-2,2-dimethylpropyl)amino]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 243

N-Cyclopropyl-4-methyl-3-[2-oxo-3-[[1-[2-[2-(1-piperazinyl)ethoxy]phenyl]cyclopropyl]amino]-1(2H)-pyrazinyl]-benzamide

Example 244

N-Cyclopropyl-3-[3-[[1-[2-[2-(3,3-difluoro-1-pyrrolidinyl)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 245

N-Cyclopropyl-3-[3-[[1-[2-[2-[(2-fluoroethyl)amino]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 246

N-Cyclopropyl-4-methyl-3-[3-[[1-[2-[2-[(1-methylpropyl)amino]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 247

N-Cyclopropyl-4-methyl-3-[3-[[1-[2-[2-[(2R)-2-methyl-1-pyrrolidinyl]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 248

3-[3-[[1-[2-[2-(cyclobutylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-Cyclopropyl-4-methyl-benzamide

Example 249

N-Cyclopropyl-3-[3-[[1-[2-[2-[[(1R)-2-hydroxy-1-methylethyl]amino]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 250

N-Cyclopropyl-3-[3-[[1-[2-[2-[(3-hydroxypropyl)amino]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 251

3-[3-[[1-[2-(2-aminoethoxy)phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide

TABLE 9

MS [M + H]⁺ Example R m/z ¹H NMR δ (DMSO-d₆ unless indicated) 231

518 8.37-8.32 (1H, m), 7.84 (1H, d), 7.68 (1H, s), 7.47 (2H, t), 7.36(1H, s), 7.19 (1H, t), 6.95 (1H, d), 6.90-6.81 (3H, m), 6.70 (1H, d),4.06 (2H, t), 3.38 (2H, t), 3.18 (3H, s), 2.99-2.91 (1H, m), 2.87- 2.69(2H, m), 2.06 (3H, s), 1.27-1.10 (6H, m), 0.73-0.61 (2H, m), 0.56-0.46(2H, m) 232

573 δ (CD₃OD) 7.81 (dd, 1H), 7.61 (d, 1H), 7.55 (dd, 1H), 7.44 (d, 1H),7.22-7.17 (m, 1H), 6.92 (d, 1H), 6.89-6.83 (m, 2H), 6.56 (d, 1H), 4.19(t, 2H), 3.61 (t, 2H), 2.92 (t, 2H), 2.84-2.76 (m, 1H), 2.76-2.65 (m,4H), 2.63-2.52 (m, 4H), 2.48 (t, 2H), 2.11 (s, 3H), 1.29-1.15 (m, 3H),1.14-1.08 (m, 1H), 0.79-0.72 (m, 2H), 0.61-0.55 (m, 2H). 233

504 8.35 (1H, d), 7.84 (1H, dd), 7.67 (1H, d), 7.52-7.43 (2H, m), 7.38(1H, s), 7.23- 7.15 (1H, m), 6.96 (1H, d), 6.89-6.82 (2H, m), 6.70 (1H,d), 4.42 (1H, t), 4.06 (2H, t), 2.96 (2H, t), 2.88-2.75 (1H, m), 2.67(2H, t), 2.06 (3H, s), 1.22-0.98 (6H, m), 0.71-0.61 (2H, m), 0.57-0.47(2H, m) 234

502 8.35 (d, 1H), 7.84 (d,1H), 7.68 (s, 1H), 7.48 (t, 2H), 7.35 (s, 1H),7.20 (t, 1H), 6.96 (d, 1H), 6.89-6.82 (m, 3H), 6.71 (d, 1H), 4.05 (t,2H), 2.94 (t, 2H), 2.87- 2.70 (m, 2H), 2.06 (s, 3H), 1.29-1.11 (m, 2H),0.98 (d, 6H), 0.88-0.79 (m, 2H), 0.71-0.61 (m, 2H), 0.56-0.46 (m, 2H)235

557 δ (CD₃OD) 7.79 (dd, 1H), 7.59 (d, 1H), 7.52 (dd, 1H), 7.42 (d, 1H),7.20-7.14 (m, 1H), 6.92-6.80 (m, 2H), 6.54 (d, 1H), 4.12 (t, 2H), 3.02(t, 2H), 2.93- 2.87 (m, 4H), 2.82-2.74 (m, 1H), 2.69- 2.62 (m, 4H), 2.27(s, 3H), 2.08 (s, 3H), 1.85-1.78 (m, 2H), 1.32-1.05 (m, 5H), 0.89-0.81(m, 1H), 0.77-0.70 (m, 2H), 0.59-0.52 (m, 2H) 236

530 δ (CD₃OD) 7.80 (dd, 1H), 7.59 (s, 1H), 7.54 (dd, 1H), 7.43 (d, 1H),7.21-7.15 (m, 1H), 6.91 (d, 1H), 6.88-6.82 (m, 2H), 6.55 (dd, 1H),4.35-4.29 (m, 1H), 4.15 (t, 2H), 3.04-2.85 (m, 4H), 2.82- 2.75 (m, 1H),2.70-2.63 (m, 2H), 2.17- 2.06 (m, 4H), 1.74-1.64 (m, 1H), 1.26- 1.15 (m,2H), 1.15-1.08 (m, 1H), 0.95- 0.81 (m, 1H), 0.78-0.71 (m, 2H), 0.59-0.54 (m, 2H) 237

488 δ (CD₃OD) 7.80 (d, 1H), 7.62-7.53 (m, 2H), 7.46-7.39 (m, 1H),7.22-7.14 (m, 1H), 6.95-6.82 (m, 2H), 6.57-6.50 (m, 1H), 4.19-4.10 (m,2H), 3.32-3.25 (m, 2H), 2.91-2.84 (m, 2H), 2.82-2.74 (m, 1H), 2.41-2.34(m, 6H), 2.12-2.05 (m, 3H), 1.32-1.07 (m, 4H), 0.78-0.71 (m, 2H),0.60-0.52 (m, 2H) 238

514 δ (CD₃OD) 7.80 (dd, 1H), 7.59 (d, 1H), 7.54 (dd, 1H), 7.43 (d, 1H),7.21-7.16 (m, 1H), 6.92 (d, 1H), 6.88-6.82 (m, 2H), 6.54 (d, 1H), 4.17(t, 2H), 3.01 (t, 2H), 2.83-2.76 (m, 1H), 2.75-2.68 (m, 3H), 2.09 (s,3H), 1.83-1.77 (m, 4H), 1.25-1.15 (m, 3H), 1.15-1.08 (m, 1H), 0.90-0.81(m, 1H), 0.78-0.71 (m, 2H), 0.59-0.54 (m, 2H) 239

544 δ (CD₃OD) 7.83 (d, 1H), 7.63 (s, 1H), 7.56 (d, 1H), 7.46 (d, 1H),7.21 (t, 1H), 6.94 (d, 1H), 6.91-6.84 (m, 2H), 6.58 (d, 1H), 4.20-4.14(m, 2H), 3.62-3.48 (m, 2H), 3.43-3.35 (m, 2H), 2.92-2.79 (m, 2H),2.74-2.66 (m, 1H), 2.54-2.43 (m, 1H), 2.12 (s, 3H), 1.99-1.87 (m, 1H),1.82-1.73 (m, 2H), 1.70-1.60 (m, 1H), 1.32-1.08 (m, 4H), 0.92-0.84 (m,1H), 0.81-0.74 (m, 2H), 0.63-0.57 (m, 2H) 240

542 δ (CD₃OD) 7.91-7.86 (m, 1H), 7.76- 7.71 (m, 1H), 7.70-7.65 (m, 1H),7.57- 7.51 (m, 1H), 7.42-7.35 (m, 1H), 7.14- 7.09 (m, 1H), 7.08-7.03 (m,1H), 6.97- 6.92 (m, 1H), 6.88-6.83 (m, 1H), 4.40- 4.33 (m, 2H),3.80-3.71 (m, 2H), 3.57- 3.52 (m, 1H), 3.51-3.46 (m, 2H), 3.25- 3.21 (m,1H), 2.93-2.85 (m, 1H), 2.26 (s, 3H), 1.58-1.52 (m, 1H), 1.52-1.44 (m,2H), 1.41-1.34 (m, 1H), 1.28-1.21 (m, 1H), 0.89-0.83 (m, 2H), 0.70-0.64(m, 2H) 241

502 δ (CD₃OD) 7.81 (d, 1H), 7.68-7.58 (m, 2H), 7.46 (d, 1H), 7.34-7.27(m, 1H), 7.05 (d, 1H), 6.99 (t, 1H), 6.87 (d, 1H), 6.77-6.72 (m, 1H),4.47-4.40 (m, 2H), 3.77-3.59 (m, 2H), 3.50-3.43 (m, 1H), 2.93 (s, 3H),2.85-2.76 (m, 1H), 2.16 (s, 3H), 1.53-1.11 (m, 9H), 0.78 (d, 2H),0.62-0.55 (m, 2H) 242

546 δ (CD₃OD) 7.90 (d, 1H), 7.79 (s, 1H), 7.70 (d, 1H), 7.56 (d, 1H),7.45-7.39 (m, 1H), 7.16 (d, 1H), 7.10 (t, 1H), 6.95- 6.91 (m, 2H), 4.50(s, 2H), 3.70-3.58 (m, 2H), 3.58-3.55 (m, 2H), 3.21 (s, 2H), 2.93-2.86(m, 1H), 2.30 (s, 3H), 1.72-1.65 (m, 1H), 1.64-1.58 (m, 1H), 1.57-1.50(m, 1H), 1.43-1.34 (m, 1H), 1.05 (s, 6H), 0.86 (d, 2H), 0.72-0.66 (m,2H) 243

529 δ (CD₃OD) 7.80 (dd, 1H), 7.60 (d, 1H), 7.54 (dd, 1H), 7.43 (d, 1H),7.22-7.16 (m, 1H), 6.91 (d, 1H), 6.89-6.82 (m, 2H), 6.56 (d, 1H), 4.18(t, 2H), 2.90 (t, 2H), 2.85 (t, 3H), 2.82-2.76 (m, 1H), 2.66-2.59 (m,4H), 2.10 (s, 3H), 1.25- 1.08 (m, 6H), 0.90-0.81 (m, 2H), 0.79- 0.72 (m,2H), 0.60-0.55 (m, 2H) 244

550 δ (CD₃OD) 7.83-7.78 (m, 1H), 7.65 (s, 1H), 7.58 (d, 1H), 7.46 (d,1H), 7.29 (t, 1H), 7.02 (d, 1H), 6.97 (t, 1H), 6.86 (d, 1H), 6.75 (d,1H), 4.40 (t, 2H), 3.91 (q, 2H), 3.84-3.75 (m, 1H), 3.70 (t, 3H),2.85-2.76 (m, 1H), 2.50-2.36 (m, 2H), 2.17 (s, 3H), 2.01 (s, 1H),1.56-1.46 (m, 1H), 1.45-1.31 (m, 2H), 1.22-1.12 (m, 1H), 0.80-0.71 (m,2H), 0.61-0.55 (m, 2H) 245

506 δ (CD₃OD) 7.80 (d, 1H), 7.64 (s, 1H), 7.57 (d, 1H), 7.46 (d, 1H),7.31-7.23 (m, 1H), 7.03-6.93 (m, 2H), 6.87 (d, 1H), 6.70 (d, 1H),4.69-4.64 (m, 1H), 4.57-4.52 (m, 1H), 4.41-4.35 (m, 2H), 3.70-3.55 (m,2H), 3.52-3.39 (m, 2H), 2.85-2.77 (m, 1H), 2.16 (s, 3H), 2.01 (s, 1H),1.52-1.43 (m, 1H), 1.40-1.24 (m, 3H), 1.19-1.10 (m, 2H), 0.77 (d, 2H),0.63-0.54 (m, 2H) 246

516 9.03 (s, 1H), 8.45 (s, 1H), 8.27 (s, 1H), 7.85 (d, 1H), 7.75 (s,1H), 7.63 (d, 1H), 7.45 (d, 2H), 7.23-7.12 (m, 2H), 6.94- 6.77 (m, 2H),4.36-4.15 (m, 2H), 3.57- 3.33 (m, 2H), 2.91-2.74 (m, 4H), 2.13 (s, 3H),1.83-1.71 (m, 1H), 1.51-1.19 (m, 4H), 1.06-0.87 (m, 2H), 0.80-0.71 (m,3H), 0.68-0.50 (m, 4H) 247

528 8.37 (d, 1H), 9.44 (s, 1H), 7.84 (d, 1H), 7.68 (s, 1H), 7.61 (d,1H), 7.46 (d, 1H), 7.26 (t, 1H), 7.04-6.98 (m, 1H), 6.94 (t, 1H), 6.87(d, 1H), 6.73 (d, 1H), 4.39- 4.31 (m, 2H), 3.88-3.29 (m, 2H), 2.90- 2.76(m, 1H), 2.30-2.13 (m, 2H), 2.07 (s, 3H), 2.03-1.77 (m, 5H), 1.72-1.46(m, 2H), 1.31 (d, 3H), 1.14-0.99 (m, 2H), 0.73-0.60 (m, 2H), 0.55-0.48(m, 2H) 248

514 δ (CD₃OD) 7.78 (d, 1H), 7.63-7.60 (m, 1H), 7.52 (d, 1H), 7.43 (d,1H), 7.22 (t, 1H), 6.97-6.89 (m, 2H), 6.89-6.85 (m, 1H), 6.64-6.60 (m,1H), 4.30-4.25 (m, 2H), 3.82-3.72 (m, 1H), 3.49-3.40 (m, 2H), 3.38-3.33(m, 1H), 2.83-2.75 (m, 1H), 2.19-2.09 (m, 5H), 2.08-1.98 (m, 2H),1.80-1.69 (m, 2H), 1.47-1.34 (m, 1H), 1.33-1.18 (m, 2H), 1.17-1.10 (m,1H), 1.05-0.97 (m, 1H), 0.88-0.81 (m, 1H), 0.79-0.72 (m, 2H), 0.60-0.53(m, 2H) 249

518 8.34 (1H, s), 7.82 (1H, d), 7.66 (1H, s), 7.48 (1H, d), 7.43 (1H,d), 7.32 (1H, s), 7.17 (1H, t), 6.93 (1H, d), 6.86-6.81 (2H, m), 6.67(1H, d), 4.52-4.43 (1H, m), 4.11-3.95 (2H, m), 3.41-3.13 (4H, m),3.03-2.86 (2H, m), 2.85-2.77 (1H, m), 2.73-2.63 (1H, m), 2.03 (3H, s),1.24-0.96 (2H, m), 0.92 (3H, d), 0.68- 0.61 (2H, m), 0.54-0.47 (2H, m)250

518 8.35 (d, 1H), 7.84 (dd, 1H), 7.67 (d, 1H), 7.50 (dd, 1H), 7.46 (d,1H), 7.41 (s, 1H), 7.19 (td, 1H), 6.95 (d, 1H), 6.88-6.83 (m, 2H), 6.69(d, 1H), 4.05 (t, 2H), 3.44 (t, 2H), 2.93 (t, 2H), 2.82 (octet, 1H),2.66 (t, 2H), 2.06 (s, 3H), 1.56 (quintet, 2H), 1.23-1.13 (m, 3H),1.06-1.01 (m, 1H), 0.69-0.64 (m, 2H), 0.54-0.50 (m, 2H) 251

460 8.33 (d, 1H), 7.82 (dd, 1H), 7.65 (d, 1H), 7.47 (dd, 1H), 7.44-7.42(m, 2H), 7.17 (td, 1H), 6.91 (d, 1H), 6.84-6.81 (m, 2H), 6.67 (d, 1H),3.94 (t, 2H), 2.91 (t, 2H), 2.80 (octet, 1H), 2.03 (s, 3H), 1.21- 1.14(m, 3H), 1.03-1.00 (m, 1H), 0.66- 0.62 (m, 2H), 0.52-0.48 (m, 2H)

Example 252

N-Cyclopropyl-3-[3-[[1-[2-[2-(ethylamino)ethoxy]phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-5-fluoro-4-methyl-benzamide

a) 2-Chloro-5-fluoro-4-methyl-benzoic acid methyl ester

To a solution of 1-bromo-2-chloro-5-fluoro-4-methylbenzene (70 g)dissolved in ethyl acetate (400 mL) was added N,N-diisopropylethylamine(161 mL), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (5.15 g) and methanol (120 mL). The resultingmixture was stirred at 90° C. for 24 h under carbon monoxide (4 bar) ina 1.5 L autoclave. Furtherdichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (2.57g) was added and the reaction heated at 90°C. for a further 3 h. The cooled reaction mixture was evaporated todryness and the residue purified by silica chromatography, eluting with50% dichloromethane in iso-hexane to give the subtitle compound (57.7g).

¹H NMR δ (DMSO-d₆) 7.64-7.50 (m, 2H), 3.90 (s, 3H), 2.31 (s, 3H).

b) 2-Chloro-5-fluoro-4-methyl-benzoic acid

A solution of 2-chloro-5-fluoro-4-methyl-benzoic acid methyl ester(Example 252a, 57.77 g) in methanol (400 mL) was treated with sodiumhydroxide 2 M solution (285 mL) under nitrogen. The resulting mixturewas stirred at 25° C. for 1 h. The reaction mixture was extracted withdiethyl ether (discarded) and the aqueous layer diluted with 2 Mhydrochloric acid (250 mL). The reaction mixture was extracted withethyl acetate (500 mL). The combined organics were dried (MgSO₄),filtered and evaporated to afford the subtitle compound (51.6 g).

¹H NMR δ (DMSO-d₆) 13.66 (s, 1H), 7.68-7.39 (m, 2H), 2.36 (s, 3H).

c) 2-Chloro-5-fluoro-4-methyl-3-nitro-benzoic acid

A solution of 2-chloro-5-fluoro-4-methylbenzoic acid (Example 252b,51.57 g) dissolved in conc sulfuric acid (143 mL) was treated withpotassium nitrate (32.4 g) portionwise over 10 min at 0° C. undernitrogen. The resulting mixture was allowed to warm to room temperaturebefore stirring at 50° C. for 1 h. The reaction mixture was quenchedwith ice water and the precipitate was collected and dried in vacuo toafford the subtitle compound (65.5 g).

¹H NMR δ (DMSO-d₆) 7.94 (d, 1H), 2.26 (s, 3H).

d) 2-Chloro-5-fluoro-4-methyl-3-nitro-benzoic acid methyl ester

A solution of chlorotrimethylsilane (200 mL) in methanol (300 mL) wastreated with 2-chloro-5-fluoro-4-methyl-3-nitrobenzoic acid (Example252c, 65.5 g) portionwise under nitrogen. The resulting solution wasstirred at 20° C. for 16 h. Further chlorotrimethylsilane (100 mL) wasadded and the reaction heated at 50° C. for 6 h. The reaction mixturewas evaporated to afford crude product which was diluted with water andextracted with ethyl acetate (300 mL). The organic extract was dried(MgSO₄), filtered and evaporated to afford the subtitle compound (53.4g). 1H NMR δ (DMSO-d₆) 7.99 (d, 1H), 4.00 (s, 3H), 2.35 (s, 3H).

e) 3-Amino-5-fluoro-4-methyl-benzoic acid methyl ester

2-Chloro-5-fluoro-4-methyl-3-nitro-benzoic acid methyl ester (Example252d, 53 g), 5% Pd/C (9 g) and ammonium formate (80 g) were stirredtogether in ethanol (500 mL) at 75° C. for 32 h. The reaction wasfiltered through celite and filtrate evaporated to a solid. This solidresidue was dissolved in dichloromethane, washed with water. Theseparated aqueous layer was further extracted with dichloromethane(3×100 mL) and the combined organics dried (MgSO4) and evaporated.Analysis showed significant unreacted starting material. The reactionwas repeated by new 5% P/C (9 g) and ammonium formate (80 g) together inethanol (500 mL) and heating at 75° C. for 20 h. Further 5% Pd/C (9 g)and ammonium formate (80 g) were added and heating continued for 10 h.The mixture was is filtered through celite and the filter cake waswashed with further ethanol. The combined filtrates were evaporated, theresidue dissolved in dichloromethane, washed with water. The separatedaqueous layer was further extracted with dichloromethane (3×100 mL) andthe combined organics dried (MgSO₄) and evaporated to afford thesubtitle compound (34.7 g).

¹H NMR δ (CDCl₃) 7.15 (s, 1H), 7.12 (dd, 1H), 3.88 (s, 3H), 2.10 (d,3H).

f) 3-[(Cyanomethyl)amino]-5-fluoro-4-methyl-benzoic acid, methyl ester

To a stirred solution of 3-amino-5-fluoro-4-methyl-benzoic acid methylester (Example 252e, 34.7 g) in THF (300 mL) at room temperature wasadded N,N-diisopropylethylamine (61.2 mL) followed by bromoacetonitrile(24.41 mL). The mixture was heated at reflux for 16 h, furtherbromoacetonitrile (4.8 mL) and N,N-diisopropylethylamine (12.5 mL) wereadded and heating was continued for 6 h. The reaction was cooled to roomtemperature and concentrated. 1N HCl (600 mL) and dichloromethane (800mL) were added. This gave some solid precipitate which did not dissolve.Water (300 mL) was added to help identify layers. The lower organiclayer containing solid and a bit of water was separated and this organicfraction was washed with 1M HCl/brine (400 mL of 1:1 mixture) beforebeing dried (MgSO₄). A second drying (Na₂SO₄) was needed. After thedrying agent was filtered off (washed through with 400 mldichloromethane) the filtrate was concentrated (˜60 g). This wasazeotroped with toluene (400 mL) and final solvent removal gave subtitlecompound (39.4 g).

¹H NMR δ (CDCl₃) 7.30 (d, 1H), 7.17 (s, 1H), 4.24 (d, 2H), 4.15-3.99 (m,1H), 3.92 (s, 3H), 2.12 (s, 3H).

g) 3-(3,5-Dibromo-2-oxo-2H-pyrazin-1-yl)-5-fluoro-4-methyl-benzoic acid,methyl ester

To a stirred solution of oxalyl bromide (49.9 mL) in dichloromethane(600 mL) at 0° C. under nitrogen was added3-[(cyanomethyl)amino]-5-fluoro-4-methyl-benzoic acid methyl ester(Example 252f, 39.4 g) over 15 min. The mixture was allowed to warm toroom temperature and stirred for 30 min then DMF (0.275 mL) was addedand the mixture heated for 16 h at reflux. After cooling to 0° C., water(200 mL) was added over 15 min (caution) then the organic layer wasseparated, dried (MgSO₄) and evaporated. The residue was purified (SiO₂chromatography eluting with dichloromethane) to afford the subtitleproduct (48.5 g).

¹H NMR δ (DMSO-d₆) 8.11 (s, 1H), 7.94 (s, 1H), 7.85 (dd, 1.5 Hz, 1H),3.88 (s, 3H), 2.11 (d, 3H)

h)3-[5-Bromo-3-[[1-methyl-1-[2-(phenylmethoxy)phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-5-fluoro-4-methyl-benzoicacid, methyl ester

A solution of α,α-dimethyl-2-(phenylmethoxy)-benzenemethanamine (Example198d, 5.25 g) dissolved in dioxane (40 mL) was treated with3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-5-fluoro-4-methyl-benzoic acid,methyl ester (Example 252g, 9.14 g) and N,N-diisopropylethylamine (5.59mL) under nitrogen. The resulting solution was stirred at 100° C. for 10h. The reaction mixture was diluted with water (50 mL), and extractedwith ethyl acetate (100 mL×2). The organic was dried (MgSO₄), filteredand evaporated. The crude product was purified (SiO₂ chromatographyeluting with 20% ethyl acetate in iso-hexane) to afford the subtitleproduct (10.50 g).

MS: APCI(+ve) 580 (M+H)⁺.

i)3-[5-Bromo-3-[[1-methyl-1-[2-(phenylmethoxy)phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-5-fluoro-4-methyl-benzamide

A solution of3-[5-bromo-3-[[1-methyl-1-[2-(phenylmethoxy)phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-5-fluoro-4-methyl-benzoicacid, methyl ester (Example 252h, 10.50 g) dissolved in THF (100 mL) wastreated with cyclopropylamine (7.61 mL). Isopropylmagnesium chloride(45.2 mL of a 2.0M solution in THF) was added dropwise over 10 min undernitrogen. The resulting solution was stirred at 25° C. for 1 h. Thereaction mixture was diluted with saturated ammonium chloride solution(300 mL) and extracted with ethyl acetate (×3). The organic was dried(MgSO₄), filtered and evaporated. The crude product was triturated withdiethyl ether and filtered to afford the subtitle compound (9.86 g).

¹H NMR δ (DMSO-d₆) 8.54-8.47 (m, 1H), 7.78-7.64 (m, 2H), 7.46-6.91 (m,10H), 5.15 (s, 2H), 4.08-3.98 (m, 1H), 2.01-1.93 (m, 3H), 1.87 (s, 6H),0.74-0.67 (m, 2H), 0.59-0.52 (m, 2H).

j)N-Cyclopropyl-3-fluoro-5-[3-[[1-(2-hydroxyphenyl)-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

To3-[5-bromo-3-[[1-methyl-1-[2-(phenylmethoxy)phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-5-fluoro-4-methyl-benzamide(Example 252i, 9.84 g) was added 10% Pd/C (1.729 g) and ammonium formate(14.35 g). The reaction was heated at 75° C. for 2 h then filteredthrough celite and washed with ethanol. The filtrate was collected andthe volatiles removed in vacuo and the resulting crude product was takenup in dichloromethane and washed with water. The organic layer dried(MgSO₄) and the solvent removed in vacuo and the residue triturated withdiethyl ether to afford subtitle product (7.08 g).

¹H NMR δ (DMSO-d₆) 9.56-9.46 (m, H), 8.58-8.48 (m, 1H), 7.76 (d, 1H),7.71 (s, 1H), 7.24 (d, 1H), 7.07-6.97 (m, 2H), 6.81-6.65 (m, 4H),2.90-2.77 (m, 1H), 2.03 (s, 3H), 1.87-1.80 (m, 6H), 0.74-0.67 (m, 2H),0.63-0.53 (m, 2H).

k)3-[3-[[1-[2-(2-Chloroethoxy)phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-5-fluoro-4-methyl-benzamide

A solution ofN-cyclopropyl-3-fluoro-5-[3-[[1-(2-hydroxyphenyl)-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide(Example 252j, 7.08 g) dissolved in acetonitrile (150 mL) was treatedwith potassium carbonate (22.42 g) and 1-bromo-2-chloroethane (13.50 mL)under nitrogen. The resulting suspension was stirred at 83° C. for 10 h.The reaction mixture was evaporated to dryness, diluted with water (300mL), and extracted with dichloromethane. The organic layer was dried(MgSO₄) and evaporated. The crude product was triturated with 50%diethyl ether in iso-hexane to afford subtitle compound (7.58 g).

¹H NMR δ (DMSO-d₆) d 8.57-8.48 (m, 1H), 7.76 (d, 1H), 7.68 (s, 1H),7.37-7.31 (m, 1H), 7.25-7.17 (m, 1H), 6.98-6.90 (m, 3H), 6.70 (s, 2H),4.26-4.15 (m, 2H), 4.01-3.90 (m, 2H), 3.43-3.35 (m, 1H), 2.03 (s, 3H),1.90 (s, 6H), 0.74-0.66 (m, 2H), 0.60-0.52 (m, 2H).

l)N-Cyclopropyl-3-[3-[[1-[2-[2-(ethylamino)ethoxy]phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-5-fluoro-4-methyl-benzamide

A suspension of3-[3-[[1-[2-(2-chloroethoxy)phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-5-fluoro-4-methyl-benzamide(Example 252k, 0.5 g) dissolved in 1,4-dioxane (2 mL) was treated with70% ethylamine (2 mL) in a sealed tube. The resulting mixture wasstirred at 100° C. for 1 h in a microwave (100 W). Evaporation andpurification by preparative HPLC (Waters X-Terra column using a 95-5%gradient of aqueous 0.2% ammonia in acetonitrile as eluent) gave thetitle compound (0.255 g).

MS: APCI(+ve) 508 (M+H)⁺.

¹H NMR δ (DMSO-d₆) 8.57 (s, 1H), 7.75 (d, 2H), 7.69 (s, 1H), 7.40-7.29(m, 1H), 7.24-7.13 (m, 1H), 6.98-6.86 (m, 3H), 6.73-6.62 (m, 2H),4.10-3.88 (m, 2H), 3.42-3.24 (m, 1H), 2.91-2.79 (m, 2H), 2.04 (s, 3H),1.89 (s, 6H), 0.92-0.80 (m, 5H), 0.76-0.64 (m, 2H), 0.61-0.48 (m, 2H).

The following examples 253-258 (Table 10) were prepared in a similarmanner to Example 252.

Example 253

N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[(2-hydroxyethyl)amino]ethoxy]phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 254

N-Cyclopropyl-3-fluoro-4-methyl-5-[3-[[1-methyl-1-[2-[2-[(1-methylethyl)amino]ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benamide

Example 255

N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[(2-methoxyethyl)amino]ethoxy]phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 256

N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[[(2R)-2-hydroxypropyl]amino]ethoxy]phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 257

N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[(2-hydroxy-2-methylpropyl)amino]ethoxy]phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 258

N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[[(2S)-2-hydroxypropyl]amino]ethoxy]phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

TABLE 10

MS [M + H]⁺ Example R m/z ¹H NMR δ (DMSO-d₆) 253

524 8.57-8.44 (m, 1H), 7.81-7.68 (m, 1H), 7.68 (s, 1H), 7.37-7.27 (m,1H), 7.23- 7.13 (m, 1H), 7.00-6.83 (m, 3H), 6.71- 6.59 (m, 2H),4.44-4.31 (m, 1H), 4.01- 3.88 (m, 2H), 3.46-3.33 (m, 2H), 2.93- 2.80 (m,3H), 2.65-2.52 (m, 2H), 2.04 (s, 3H), 1.88 (s, 6H), 0.76-0.64 (m, 2H),0.60-0.48 (m, 2H) 254

522 8.57-8.48 (m, 1H), 7.76 (d, 1H), 7.70- 7.61 (m, 2H), 7.38-7.31 (m,1H), 7.23- 7.15 (m, 1H), 7.02-6.86 (m, 3H), 6.74- 6.64 (m, 2H),4.03-3.87 (m, 2H), 2.95- 2.79 (m, 3H), 2.77-2.61 (m, 1H), 2.05- 1.93 (m,3H), 1.90-1.78 (m, 6H), 0.96- 0.85 (m, 6H), 0.77-0.65 (m, 2H), 0.61-0.50 (m, 2H) 255

538 8.54-8.45 (m, 1H), 7.79-7.69 (m, 1H), 7.68-7.58 (m, 1H), 7.37-7.27(m, 1H), 7.22- 7.13 (m, 1H), 6.99-6.83 (m, 3H), 6.72-6.60 (m, 2H),4.03-3.88 (m, 2H), 3.38-3.28 (m, 2H), 3.20-3.10 (m, 3H), 2.91-2.81 (m,3H), 2.70-2.60 (m, 2H), 2.05 (s, 3H), 1.88 (s, 6H), 0.76-0.66 (m, 2H),0.59-0.49 (m, 2H) 256

538 8.55-8.49 (m, 1H), 7.75 (d, 1H), 7.67 (s, 1H), 7.32 (d, 1H),7.22-7.16 (m, 1H), 6.99-6.86 (m, 3H), 6.71-6.64 (m, 2H), 4.37-4.30 (m,1H), 4.02-3.89 (m, 2H), 3.63-3.56 (m, 1H), 2.90 2.83 (m, 3H), 2.43 (d,2H), 1.96 (s, 3H), 1.87- 1.81 (m, 6H), 0.97 (d, 3H), 0.72-0.66 (m, 2H),0.59-0.53 (m, 2H) 257

552 8.55-8.48 (m, 1H), 7.74 (d, 1H), 7.61 (s, 1H), 7.33 (d, 1H),7.24-7.15 (m, 1H), 7.01-6.84 (m, 3H), 6.72-6.62 (m, 2H), 4.05 (s, 1H),4.03-3.90 (m, 2H), 2.95-2.82 (m, 3H), 2.39 (s, 2H), 1.96 (s, 3H), 1.81(s, 6H), 1.01 (s, 6H), 0.73- 0.67 (m, 2H), 0.58-0.53 (m, 2H) 258

538 8.56-8.46 (m, 1H), 7.76 (d, 1H), 7.62 (s, 1H), 7.32 (d, 1H),7.22-7.15 (m, 1H), 6.97-6.86 (m, 3H), 6.70-6.65 (m, 2H), 4.37-4.33 (m,1H), 4.02-3.90 (m, 2H), 3.63-3.55 (m, 1H), 2.91-2.82 (m, 3H), 2.43 (d,2H), 2.02 (s, 3H), 1.85- 1.80 (m, 6H), 0.97 (d, 3H), 0.72-0.66 (m, 2H),0.58-0.53 (m, 2H)

Example 259

N-Cyclopropyl-3-fluoro-4-methyl-5-[3-[[1-[2-[2-(methylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

a)3-[5-bromo-2-oxo-3-[[1-[2-(phenylmethoxy)phenyl]cyclopropyl]amino]-1(2H)-pyrazinyl]-5-fluoro-4-methyl-benzoicacid, methyl ester

A solution of 1-(2-(benzyloxy)phenyl)cyclopropanamine (Example 167a, 5g)in dioxane (200 mL) was treated with3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-5-fluoro-4-methyl-benzoic acid,methyl ester (Example 252g, 7.5 g) and N-ethyldiisopropylamine (5.36 mL)under nitrogen. The resulting solution was stirred at 100° C. for 8 h.The cooled reaction mixture was diluted with 2M HCl (300 mL), andextracted with ether (3×300 mL). The combined organics were dried(MgSO₄), filtered and evaporated to afford crude product. Purification(SiO₂ chromatography eluting with 20% ethyl acetate in iso-hexane) gavethe subtitle compound. (9.20 g).

¹H NMR δ (DMSO-d₆) 7.82-7.76 (m, 2H), 7.59-7.49 (m, 3H), 7.41-7.26 (m,3H), 7.24-7.15 (m, 1H), 7.06-6.98 (m, 2H), 6.89 (t, 1H), 5.22 (s, 1H),3.85 (s, 2H), 3.31 (s, 3H), 2.03 (d, 3H), 1.25-1.07 (m, 4H).

b)3-Fluoro-5-[3-[[1-(2-hydroxyphenyl)cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoicacid, methyl ester

To3-[5-bromo-2-oxo-3-[[1-[2-(phenylmethoxy)phenyl]cyclopropyl]amino]-1(2H)-pyrazinyl]-5-fluoro-4-methyl-benzoicacid, methyl ester (Example 259a, 9.2 g) in ethanol (400 mL) was addedammonium formate (14.04 g) and 10% Pd/C (1.693 g). The reaction washeated at 75° C. for 1 h, filtered through celite washing the celitewith further warm ethanol (100 mL) followed by dichloromethane (2000 mL)and the combined filtrates were evaporated, diluted with dichloromethane(1000 mL) and washed with water, dried (MgSO₄) and evaporated to givethe subtitle compound (6.16 g).

¹H NMR δ (DMSO-d₆) 11.23 (s, 1H), 7.85-7.73 (m, 2H), 7.48-7.42 (m, 1H),7.16-7.04 (m, 1H), 6.91-6.86 (m, 1H), 6.83-6.67 (m, 3H), 5.75 (s, 1H),3.85 (s, 3H), 2.03 (s, 3H), 1.32-1.16 (m, 2H), 1.12-1.01 (m, 2H).

c)N-Cyclopropyl-3-fluoro-5-[3-[[1-(2-hydroxyphenyl)cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Isopropylmagnesium chloride (30.1 ml of a 2M solution in THF) was addedover 20 min to a solution of cyclopropylamine (10.61 mL) and3-fluoro-5-[3-[[1-(2-hydroxyphenyl)cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoicacid methyl ester (Example 259b, 6.16 g) in tetrahydrofuran (200 mL) andthe reaction stirred at room temperature under nitrogen for 1 h. Water(100 mL) and 2M HCl (200 mL) were cautiously added and the aqueous layerextracted with dichloromethane (3×200 mL) and the combined organicextracts dried (MgSO₄) and the solvent removed to give the subtitlecompound (5.00 g).

¹H NMR δ (DMSO-d₆) 11.14 (s, 1H), 8.52 (s, 1H), 8.46 (d, 1H), 7.74 (dd,1H), 7.64 (s, 1H), 7.46 (dd, 1H), 7.13-7.08 (m, 1H), 6.91 (d, 1H),6.82-6.72 (m, 3H), 2.88-2.78 (m, 1H), 1.99 (d, 3H), 1.30-1.20 (m, 2H),0.88-0.79 (m, 2H), 0.70-0.63 (m, 2H), 0.55-0.50 (m, 2H).

d)3-[3-[[1-[2-(2-chloroethoxy)phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-5-fluoro-4-methyl-benzamide

N-Cyclopropyl-3-fluoro-5-[3-[[1-(2-hydroxyphenyl)cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide(Example 259c 5 g), 1-bromo-2-chloroethane (9.58 mL) and cesiumcarbonate (37.5 g) were stirred together in acetonitrile (200 mL) at 80°C. under nitrogen for 16 h. The cooled reaction mixture was evaporatedto dryness, diluted with water (500 mL) and extracted withdichloromethane (3×300 mL). The combined organics were dried (MgSO₄),filtered and evaporated. The residue was triturated with 1:1iso-hexane:diethyl ether to give the subtitle compound (4.60 g).

¹H NMR δ (DMSO-d₆) 8.45 (d, 1H), 7.72 (d, 1H), 7.60 (s, 1H), 7.51 (d,1H), 7.27 (s, 1H), 7.24-7.16 (m, 1H), 7.00-6.84 (m, 2H), 6.75 (d, 1H),4.30 (t, 2H), 4.00 (t, 2H), 2.93-2.77 (m, 1H), 1.95 (s, 3H), 1.31-1.02(m, 4H), 0.75-0.62 (m, 2H), 0.58-0.47 (m, 2H).

e)N-Cyclopropyl-3-fluoro-4-methyl-5-[3-[[1-[2-[2-(methylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

3-[3-[[1-[2-(2-chloroethoxy)phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-5-fluoro-4-methyl-benzamide(Example 259d 0.5 g) and 40% methylamine in water (0.697 mL) were heatedat 100° C. in dioxane (8 mL) in a sealed tube for 24 h. Purification ofthe cooled solution by preparative HPLC (Xbridge column—acetonitrile/0.2% ammonia mobile phase) gave the title compound (270mg).

MS: APCI(+ve) 492 (M+H)⁺.

¹H NMR δ (DMSO-d₆) 8.45 (1H, d), 7.73 (1H, d), 7.60 (1H, s), 7.52-7.47(2H, m), 7.23-7.15 (1H, m), 6.95 (1H, d), 6.89-6.82 (2H, m), 6.73 (1H,d), 4.05 (2H, t), 2.89 (2H, t), 2.85-2.77 (1H, m), 2.35 (3H, s), 1.96(3H, d), 1.25-0.97 (4H, m), 0.73-0.62 (2H, m), 0.57-0.48 (2H, m).

Example 260

N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[(2-hydroxyethyl)amino]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

3-[3-[[1-[2-(2-chloroethoxy)phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-5-fluoro-4-methyl-benzamide(Example 259d, 5 g) and ethanolamine (6.1 mL) were heated at 100° C. indioxane (20 mL) in a sealed tube for 16 h. Purification of the cooledsolution by preparative HPLC (Xterra column, eluting with a gradient ofacetonitrile in 0.2% (v/v) aqueous ammonia) gave the title product (2.95g) after solvent removal and trituration with isohexane/diethyl ether(1:1 80 mL)

MS: APCI(+ve) 522 (M+H)⁺.

¹H NMR δ (DMSO-d₆) 8.46 (1H, d), 7.73 (1H, d), 7.61 (1H, s), 7.51 (1H,d), 7.43 (1H, s), 7.19 (1H, t), 6.95 (1H, d), 6.92-6.80 (2H, m), 6.74(1H, d), 4.44 (1H, s), 4.06 (2H, t), 3.51-3.43 (2H, m), 3.42-3.30 (1H,m), 2.97 (2H, t), 2.90-2.77 (1H, m), 2.69 (2H, t), 1.97 (3H, s),1.27-1.01 (4H, m), 0.75-0.63 (2H, m), 0.57-0.50 (2H, m).

The following examples 261-265 (Table 11) were prepared in a similarmanner to Examples 259 and 260:

Example 261

N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[(2-methoxyethyl)amino]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 262

N-Cyclopropyl-3-[3-[[1-[2-[2-(ethylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-5-fluoro-4-methyl-benzamide

Example 263

N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[[(2S)-2-hydroxypropyl]amino]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Example 264

N-Cyclopropyl-3-fluoro-4-methyl-5-[3-[[1-[2-[2-[(1-methylethyl)amino]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

Example 265

N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[[(2R)-2-hydroxypropyl]amino]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

TABLE 11

MS [M + H]⁺ Example R m/z ¹H NMR δ (DMSO-d₆) 261

536 8.47 (1H, d), 7.75 (1H, d), 7.63 (1H, s), 7.51 (1H, d), 7.42 (1H,s), 7.20 (1H, t), 6.96 (1H, d), 6.92-6.83 (2H, m), 6.75 (1H, d), 4.07(2H, t), 3.40 (3H, t), 3.00- 2.94 (2H, m), 2.90-2.81 (1H, m), 2.76 (2H,t), 1.98 (3H, s), 1.20 (3H, s), 1.13- 0.78 (4H, m), 0.74-0.64 (2H, m),0.60- 0.49 (2H, m) 262

506 8.45 (1H, d), 7.73 (1H, d), 7.61 (1H, s), 7.52-7.42 (2H, m), 7.19(1H, t), 6.95 (1H, d), 6.91-6.81 (2H, m), 6.74 (1H, d), 4.05 (2H, t),2.94 (2H, t), 2.89-2.78 (1H, m), 2.63 (2H, q), 1.97 (3H, s), 1.25- 1.08(4H, m), 1.00 (3H, t), 0.72-0.63 (2H, m), 0.57-0.51 (2H, m) 263

536 8.44 (1H, d), 7.72 (1H, dd), 7.60 (1H, s), 7.49 (1H, dd), 7.39 (1H,d), 7.22-7.17 (1H, m), 6.96 (1H, d), 6.89-6.83 (2H, m), 6.73 (1H, d),4.41-4.38 (1H, m), 4.10-4.02 (2H, m), 3.72-3.63 (1H, m), 2.98-2.91 (2H,m), 2.86-2.76 (1H, m), 1.96 (3H, s), 1.25-1.13 (4H, m), 1.02 (3H, dd),0.88-0.80 (2H, m), 0.71-0.64 (2H, m), 0.56-0.49 (2H, m) 264

520 8.44 (1H, d), 7.72 (1H, dd), 7.60 (1H, s), 7.49 (1H, dd), 7.37 (1H,s), 7.23-7.15 (1H, m), 6.95 (1H, d), 6.89-6.82 (2H, m), 6.74 (1H, d),4.04 (2H, t), 2.94 (2H, t), 2.88-2.73 (2H, m), 1.96 (3H, d), 1.20- 1.16(2H, m), 0.98 (6H, d), 0.87-0.80 (2H, m), 0.72-0.63 (2H, m), 0.57-0.49(2H, m) 265

536 8.42 (1H, s), 7.74-7.63 (1H, m), 7.61- 7.54 (1H, m), 7.51-7.34 (2H,m), 7.20- 7.07 (1H, m), 6.96-6.76 (2H, m), 6.74- 6.66 (1H, m), 4.45-4.32(1H, m), 4.08- 3.95 (2H, m), 3.72-3.56 (1H, m), 3.41- 3.21 (1H, m),3.02-2.71 (6H, m), 1.93 (3H, s), 1.27-0.88 (6H, m), 0.73-0.36 (4H, m)

Example 266

N-Cyclopropyl-3-[3-[[1-[2-[2-(ethylamino)ethoxy]phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

a) 3,3-Diethyl-2(3H)-benzofuranone

Benzofuran-2(3H)-one (2 g) in DMF (3.5 mL) was added dropwise to 60%sodium hydride (1.252g) in DMF (10 mL) at 0° C. and after 20 min, ethyliodide (5.18 mL) was added dropwise and the reaction warmed to roomtemperature and stirred for 20 h. The solids were filtered off andwashed with ethyl acetate. The filtrate was acidified with 2Mhydrochloric acid, and then extracted with ethyl acetate. The combinedorganic layers were dried (MgSO₄) and concentrated in vacuo. The crudeproduct was purified (SiO₂ chromatography eluting with 20% diethyl etherin iso-hexane) to afford the subtitle product (1.14g).

¹H NMR δ (DMSO-d₆) 7.41-7.34 (m, 2H), 7.27-7.22 (m, 2H), 1.90 (dseptet,4H), 0.58 (t, 6H).

b) α,α-Diethyl-2-hydroxy-benzeneacetamide

7N Ammonia in methanol (10 mL) was added to3,3-diethyl-2(3H)-benzofuranone (Example 266a, 1.14 g) and the reactionstirred at room temperature for 16 h. 880 Ammonia (20 mL) was added andthe mixture stirred for 5 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried (MgSO₄),filtered and evaporated to afford crude product (1.21g).

¹H NMR δ (CDCl₃) 7.47-7.44 (m, 1H), 7.40-7.35 (m, 1H), 7.00-6.93 (m,2H), 5.10 (s, 2H), 2.19 (dt, 2H), 1.93 (dt, 2H), 0.73 (t, 6H).

c) α,α-Diethyl-2-(phenylmethoxy)-benzeneacetamide

A solution of α,α-diethyl-2-hydroxy-benzeneacetamide (Example 266b, 1.21g) in DMF (9.93 mL) was treated with potassium carbonate (0.807g) andbenzyl bromide (0.694 mL) under nitrogen. The resulting mixture wasstirred at room temperature for 16 h. The reaction mixture was dilutedwith water and extracted with ethyl acetate. The organic layer was dried(MgSO₄), filtered and evaporated. The crude product was purified (SiO₂chromatography eluting with 30-100% ethyl acetate in iso-hexane) toafford the subtitle product (0.77g).

MS: APCI(+ve) 298 (M+H)⁺.

d) α,α-diethyl-2-(phenylmethoxy)-benzenemethanamine

A solution of α,α-diethyl-2-(phenylmethoxy)-benzeneacetamide (Example266c, 0.77 g) in acetonitrile (6 mL) and water (6 mL) was treated with(bis(trifluoroacetoxy)iodo)benzene (1.113 g) under nitrogen and thereaction stirred at room temperature for 16 h. Further(bis(trifluoroacetoxy)iodo)benzene (1.0g) was added and the reactionstirred for 3 h. The reaction mixture was diluted with water andextracted with ethyl acetate. The organic layer was dried (MgSO₄),filtered and evaporated. The crude product was purified on SCX resineluting with methanol (discarded) followed by 7N NH₃ in methanol. Thebasic fractions were collected and the volatiles were removed in vacuoto afford subtitle compound (0.83g).

¹H NMR δ (CDCl₃) 7.43-7.34 (m, 7H), 6.98-6.94 (m, 4H), 5.12 (s, 2H),2.13 (dt, 4H), 0.74 (t, 6H).

e)3-[3-[[1-[2-(2-Chloroethoxy)phenyl]-1-ethylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide

α,α-Diethyl-2-(phenylmethoxy)-benzenemethanamine (Example 266d) wasconverted toN-cyclopropyl-3-[3-[[1-ethyl-1-(2-hydroxyphenyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamideusing the method described in Example 134. This phenol was alkylatedwith 1-bromo-2-chloroethane as described in example 167e to afford thesubtitle product.

MS: APCI(+ve) 509 (M+H)⁺.

f)N-Cyclopropyl-3-[3-[[1-[2-[2-(ethylamino)ethoxy]phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

The title compound was prepared from3-[3-[[1-[2-(2-Chloroethoxy)phenyl]-1-ethylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide(Example 266e) using the method of example 167f.

MS: APCI(+ve) 504 (M+H)⁺.

¹H NMR δ (DMSO-d₆) 8.48-8.42 (m, 1H), 7.87 (d, 1H), 7.78 (s, 1H), 7.48(d, 1H), 7.29 (d, 1H), 7.23-7.16 (m, 1H), 7.01-6.88 (m, 3H), 6.67-6.61(m, 2H), 4.01-3.89 (m, 2H), 2.89-2.76 (m, 3H), 2.47-2.27 (m, 4H), 2.26(s, 3H), 2.11 (s, 3H), 0.71-0.61 (m, 8H), 0.57-0.52 (m, 2H).

Example 267

N-Cyclopropyl-3-[3-[[1-ethyl-1-[2-[2-(ethylamino)ethoxy]phenyl]propyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

The title compound was prepared from3-[3-[[1-[2-(2-chloroethoxy)phenyl]-1-ethylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide(Example 266e) using the method described in Example 167f but using 70%ethylamine in water.

MS: APCI(+ve) 518 (M+H)⁺.

¹H NMR δ (DMSO-d₆) 8.44 (d, 1H), 7.86 (d, 1H), 7.77 (s, 1H), 7.49 (d,1H), 7.28 (d, 1H), 7.23-7.16 (m, 1H), 7.00-6.89 (m, 3H), 6.70-6.58 (m,2H), 4.00-3.89 (m, 2H), 2.90-2.78 (m, 3H), 2.54-2.25 (m, 6H), 2.11 (s,3H), 0.89 (t, 3H), 0.70-0.62 (m, 8H), 0.59-0.51 (m, 2H).

Example 268

N-Cyclopropyl-4-methyl-3-[3-[[1-[2-[2-(methylamino)ethoxy]phenyl]cyclobutyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

a) 1-(2-Methoxyphenyl)cyclobutanecarboxamide

To 1-(2-methoxyphenyl)cyclobutanecarbonitrile (4.29 g) was addedsulfuric acid (20 mL, 95-98%)/water (20 mL) and the reaction warmed to60° C. After 1 h the solution was warmed to 80° C. and heating wascontinued for 3 h. The reaction was cooled to room temperature andstirred for 16 h. Heating was resumed and after 1 h acetic acid (10 mL)was added. The temperature was increased to 90° C. and heating wascontinued for 1.75 h. The reaction was cooled to room temperature andthen poured onto ˜300 ml of ice and extracted with ethyl acetate. Theorganic layer was dried (Na₂SO₄) and the solvent removed in vacuo toafford the subtitle product (4.19 g).

¹H NMR δ (CDCl₃) 8.44 (s, 2H), 7.27 (td, 1H), 7.23 (dd, 1H), 6.99 (td,1H), 6.90 (d, 1H), 3.83 (s, 3H), 2.87-2.77 (m, 2H), 2.51-2.41 (m, 2H),2.24-2.11 (m, 1H), 1.88-1.77 (m, 1H).

b) 1-(2-(Benzyloxy)phenyl)cyclobutanecarboxamide

To 1-(2-methoxyphenyl)cyclobutanecarboxamide (Example 268a, 4.19 g) at0° C. in dichloromethane (20 mL) was added boron tribromide (40.8 mL, 1M in dichloromethane) and the reaction warmed to room temperature over 3h. It was poured into ice, extracted with dichloromethane (×3) and thecombined organics were dried (MgSO₄) and the solvent was removed invacuo to give crude 1-(2-hydroxyphenyl)cyclobutanecarboxamide (2.96 g).This was dissolved in DMF (20 mL) and potassium carbonate (2.14 g) andbenzyl bromide (1.84 mL) were added and the reaction stirred for 16 h.Water and ethyl acetate were added and the organic layer separated. Theaqueous layer was extracted further with ethyl acetate. The combinedorganics were washed with water (×3), brine, dried (Na₂SO₄) and thesolvent was removed in vacuo. The residue was purified (SiO₂chromatography eluting with 5-50% ethyl acetate in iso-hexane) to affordthe subtitle product (1.98 g).

¹H NMR δ (CDCl₃) 7.43-7.21 (m, 7H), 7.02-6.95 (m, 2H), 5.73 (s, 1H),5.10 (s, 2H), 5.04 (s, 1H), 2.88-2.78 (m, 2H), 2.55-2.44 (m, 2H), 2.16(sextet, 1H), 1.88-1.74 (m, 1H).

c) 1-(2-(Benzyloxy)phenyl)cyclobutanamine

A solution of 1-(2-(benzyloxy)phenyl)cyclobutanecarboxamide (Example268b 1.984 g) dissolved in acetonitrile (16 mL) and water (16 mL) undernitrogen was treated with [bis(trifluoroacetoxy)iodo]benzene (4.55 g).The resulting solution was stirred at room temperature for 16 h. Thereaction mixture was diluted with water, extracted with diethyl ether.The aqueous layer was separated, basified to pH13 with aqueous 1N NaOHand extracted with ethyl acetate. The combined diethyl ether/ethylacetate organic extracts were dried (MgSO₄), filtered and the solventwas removed in vacuo. The residue was dissolved in dichloromethane andand loaded on to an SCX cartridge. The impurities were washed throughwith ethyl acetate then methanol and discarded. Elution with 7Nmethanolic ammonia and evaporation in vacuo gave the subtitle product(1.164 g).

¹H NMR δ (CDCl₃) 7.46-7.29 (m, 5H), 7.19 (t, 2H), 6.96-6.91 (m, 2H),5.10 (s, 2H), 2.62-2.42 (m, 2H), 2.28-2.06 (m, 3H), 1.85-1.63 (m, 1H).

d) Methyl3-(3-(1-(2-(benzyloxy)phenyl)cyclobutylamino)-5-bromo-2-oxopyrazin-1(2H)-yl)-4-methylbenzoate

To 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methylester (Example 1 b, 1.083 g) in dioxane (6 mL) was added1-(2-(benzyloxy)phenyl)cyclobutanamine (Example 268c, 1.16 g) andN,N-diisopropylethylamine (0.76 mL) and the reaction heated at 100° C.for 16 h. After cooling to room temperature, the reaction mixture wasdiluted with ethyl acetate and water, and the organic layer wasseparated, dried (MgSO₄), filtered and the crude product purified (SiO₂chromatography eluting with 20-50% ethyl acetate in iso-hexane) toafford the subtitle product (1.46 g).

¹H NMR δ (DMSO-d₆) 7.95 (dd, 1H), 7.86 (d, 1H), 7.58-7.40 (m, 4H),7.38-7.28 (m, 4H), 7.20 (td, 1H), 7.02 (d, 1H), 6.97-6.91 (m, 1H), 6.95(s, 1H), 5.13 (s, 2H), 3.84 (s, 3H), 2.73-2.57 (m, 4H), 2.13 (s, 3H),2.09-1.94 (m, 1H), 1.80-1.65 (m, 1H).

e)3-(3-(1-(2-(Benzyloxy)phenyl)cyclobutylamino)-5-bromo-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-4-methylbenzamide

A solution of methyl3-(3-(1-(2-(benzyloxy)phenyl)cyclobutylamino)-5-bromo-2-oxopyrazin-1(2H)-yl)-4-methylbenzoate(Example 268d, 1.46 g) in THF (40 mL) under nitrogen was treated withcyclopropylamine (0.88 mL) followed by isopropylmagnesium chloride (3.81mL, 2.0 M in THF) dropwise over 10 min. The reaction was stirred at roomtemperature for 1 h then diluted with saturated aqueous ammoniumchloride solution (300 mL) and extracted with ethyl acetate (×3). Thecombined organics were dried (MgSO₄), filtered and evaporated to affordthe subtitle product (1.537 g).

MS: APCI(+ve) 599 (M+H)⁺.

f)N-Cyclopropyl-3-(3-(1-(2-hydroxyphenyl)cyclobutylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzamide

To3-(3-(1-(2-(benzyloxy)phenyl)cyclobutylamino)-5-bromo-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-4-methylbenzamide(Example 268e, 1.537 g) in ethanol (16 mL) was added ammonium formate(2.263 g) and 5% Pd/C (0.546 g) and the reaction heated at 75° C. for 1h. The mixture was filtered through celite and the solid washed throughwith ethanol and dichloromethane. The filtrate was collected and thevolatiles removed in vacuo. The residue was purified (SiO₂chromatography eluting with 0-30% diethyl ether in dichloromethane) toafford the subtitle product (0.874 g).

MS: APCI(+ve) 431 (M+H)⁺.

g)3-(3-(1-(2-(2-Chloroethoxy)phenyl)cyclobutylamino)-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-4-methylbenzamide

ToN-cyclopropyl-3-(3-(1-(2-hydroxyphenyl)cyclobutylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzamide(Example 268f, 0.874 g) in acetonitrile (17 mL) was added1-bromo-2-chloroethane (1.68 mL) and cesium carbonate (6.61 g) and thereaction heated at 90° C. for 18 h. Ethyl acetate and water were addedand the organic layer separated, washed with water, brine, dried(MgSO₄), filtered and the solvent removed in vacuo. Purification (SiO₂chromatography eluting with 50-70% ethyl acetate/iso-hexane) gave thesubtitle product (304 mg). The drying agent was re-washed withdichloromethane (2×50 mL) and the solvent removed to afford furthersubtitle product (472 mg).

MS: APCI(+ve) 493 (M+H)⁺.

h)N-Cyclopropyl-4-methyl-3-[3-[[1-[2-[2-(methylamino)ethoxy]phenyl]cyclobutyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

The title product was prepared from3-(3-(1-(2-(2-chloroethoxy)phenyl)cyclobutylamino)-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-4-methylbenzamide(Example 268g) and methylamine using a similar method to that describedfor example 167f.

MS: APCI(+ve) 488 (M+H)⁺.

¹H NMR δ (DMSO-d₆) 8.37 (d, 1H), 7.85 (d, 1H), 7.69 (s, 1H), 7.48 (t,2H), 7.24 (s, 1H), 7.18 (t, 1H), 6.96-6.88 (m, 2H), 6.73 (d, 1H), 6.62(d, 1H), 3.99 (t, 2H), 2.87 (t, 2H), 2.89-2.78 (m, 1H), 2.74-2.55 (m,4H), 2.33 (s, 3H), 2.07 (s, 3H), 2.11-1.97 (m, 1H), 1.86-1.64 (m, 1H),0.72-0.62 (m, 2H), 0.57-0.48 (m, 2H).

Example 269

N-Cyclopropyl-3-[3-[[1-[2-[2-(ethylamino)ethoxy]phenyl]cyclobutyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

The title product was prepared from3-(3-(1-(2-(2-chloroethoxy)phenyl)cyclobutylamino)-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-4-methylbenzamide(Example 268g) and ethylamine using a similar method to that describedfor example 167f.

MS: APCI(+ve) 502 (M+H)+.

¹H NMR δ (DMSO-d₆) 8.36 (d, 1H), 7.85 (dd, 1H), 7.69 (d, 1H), 7.51-7.45(m, 2H), 7.20-7.16 (m, 2H), 6.96-6.88 (m, 2H), 6.74 (d, 1H), 6.63 (d,1H), 3.98 (t, 2H), 2.89 (t, 2H), 2.85-2.80 (m, 1H), 2.69 (t, 3H),2.60-2.54 (m, 2H), 2.50 (d, 2H), 2.06 (s, 4H), 1.80-1.71 (m, 1H), 0.96(t, 3H), 0.69-0.64 (m, 2H), 0.54-0.51 (m, 2H)

Example 270

N-Cyclopropyl-3-[3-[[1-[2-[2-[(2-hydroxyethyl)amino]ethoxy]phenyl]cyclobutyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

The title product was prepared from3-(3-(1-(2-(2-chloroethoxy)phenyl)cyclobutylamino)-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-4-methylbenzamide(Example 268g) and ethanolamine using a similar method to that describedfor example 167f.

MS: APCI(+ve) 518 (M+H)+.

¹H NMR δ (DMSO-d₆) 8.37 (d, 1H), 7.84 (d, 1H), 7.69 (s, 1H), 7.49 (q,2H), 7.31 (s, 1H), 7.19 (t, 1H), 6.93 (q, 2H), 6.73 (d, 1H), 6.62 (d,1H), 4.07 (s, 2H), 3.49 (s, 2H), 3.09 (s, 2H), 2.70 (s, 7H), 2.08 (s,5H), 0.67 (d, 2H), 0.53 (d, 2H)

Example 271

N-Cyclopropyl-4-methyl-3-[3-[[1-[2-[2-[(1-methylethyl)amino]ethoxy]phenyl]cyclobutyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamide

The title product was prepared from3-(3-(1-(2-(2-chloroethoxy)phenyl)cyclobutylamino)-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-4-methylbenzamide(Example 268g) and isopropylamine using a similar method to thatdescribed for example 167f.

MS: APCI(+ve) 516 (M+H)+.

¹H NMR δ (DMSO-d₆) 8.37 (s, 1H), 7.84 (d, 1H), 7.69 (s, 1H), 7.49 (q,2H), 7.27 (s, 1H), 7.19 (t, 1H), 6.98-6.89 (m, 2H), 6.83 (s, 1H), 6.63(s, 1H), 4.05 (s, 2H), 3.05-2.96 (m, 3H), 2.83-2.83 (m, 1H), 2.71 (s,4H), 2.08 (s, 3H), 1.84-1.69 (m, 2H), 1.02 (s, 6H), 0.67 (d, 2H), 0.53(d, 2H)

Example 272

N-Cyclopropyl-3-[3-[[(1R,2R)-3-hydroxy-1-(2-methylphenyl)-2-methylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

a)N-[(1R,2R)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2-methyl-1-(2-methylphenyl)propyl]-2-methyl-2-propanesulfinamide

The title compound was prepared from(2S)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-N-methoxy-N,2-dimethyl-propanamide(Example 136a) and o-tolylmagnesium chloride using methods described inthe Example 136b.

¹H NMR δ (CDCl₃) 7.63-7.58 (2H, m), 7.53-7.48 (2H, m), 7.42-7.27 (6H,m), 7.19-7.10 (4H, m), 4.86 (1H, dd), 3.59 (1H, d), 3.53 (1H, dd), 3.42(1H, dd), 2.38 (3H, s), 2.14-2.04 (1H, m), 1.14 (9H, s), 1.03 (9H, s),0.91 (3H, d).

b)3-[3-[[(1R,2R)-3-hydroxy-2-methyl-1-(2-methylphenyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoicacid methyl ester

The title compound was prepared fromN-[(1R,2R)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2-methyl-1-(2-methylphenyl)propyl]-2-methyl-2-propanesulfinamide(Example 272a) using the method described in the Example 136c.

¹H NMR δ (DMSO-d₆) 7.96 (2H, d), 7.85 (s, 1H), 7.80 (1H, s), 7.61-7.48(3H, m), 7.30 (2H, d), 7.23 (2H, t), 7.01 (2H, d), 6.91 (2H, t), 6.79(2H, d), 6.68 and 6.67 (2H, 2×d), 5.37 (1H, q), 4.66-4.59 (1H, m),3.88-3.76 (4H, m), 3.29-3.12 (2H, m), 2.24-2.10 (1H, m), 2.16 and 2.09(3H, 2×s), 0.86 (3H, d).

c)N-Cyclopropyl-3-[3-[[(1R,2R)-3-hydroxy-1-(2-methylphenyl)-2-methylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

The title compound was prepared from3-[3-[[(1R,2R)-3-hydroxy-2-methyl-1-(2-methylphenyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoicacid, methyl ester (Example 272b) using the method described in theExample 136d.

MS: APCI(+ve) 447 (M+H⁺).

¹H NMR δ (DMSO-d₆) 8.45 and 8.36 (1H, 2×d), 7.89-7.82 (1H, m), 7.78-7.61(2H, m), 7.55-7.44 (2H, m), 7.20-7.05 (3H, m), 6.82-6.76 (1H, m),6.67-6.61 (1H, m), 5.26 (1H, t), 4.71-4.60 (1H, 2×t), 3.29-3.05 (2H, m),2.93-2.76 (1H, m), 2.56-2.46 (3H, overlapped with DMSO), 2.28-2.13 (1H,m), 2.13 and 2.04 (3H, 2×s), 0.98-0.91 (3H, m), 0.74-0.48 (4H, m).

Example 273

N-Cyclopropyl-3-[3-[[(1R,2R)-3-hydroxy-1-(3-methylphenyl)-2-methylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

a)N-[(1R,2R)-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-2-methyl-1-(3-methylphenyl)propyl]-2-methyl-2-propanesulfinamide

The title compound was prepared from(2S)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-N-methoxy-N,2-dimethyl-propanamide(Example 136a) and m-tolylmagnesium chloride using methods described inthe Example 136b.

¹H NMR δ (CDCl₃) 7.67-7.61 (2H, m), 7.59-7.53 (2H, m), 7.46-7.30 (6H,m), 7.20 (1H, t), 7.11-7.02 (3H, m), 4.53 (1H, dd), 3.83 (1H, d), 3.54(1H, dd), 3.39 (1H, dd), 2.33 (3H, s), 2.26-2.14 (1H, m), 1.17 (9H, s),1.06 (9H, s), 0.90 (3H, d).

b) N-Cyclopropyl-3-[3-[[(1R,2R)-3-hydroxy-1-(3-methylphenyl)-2-methylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

The title compound was prepared fromN-[(1R,2R)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2-methyl-1-(3-methylphenyl)propyl]-2-methyl-2-propanesulfinamide(Example 273a) using methods described in the Example 136c and 136d.

MS: APCI(+ve) 447 (M+H⁺).

¹H NMR δ (DMSO-d₆) 8.44 and 8.38 (1H, 2×d), 7.91-7.79 (2H, m), 7.75 and7.69 (1H, 2×d), 7.49 and 7.47 (1H, 2×d), 7.24-7.13 (3H, m), 7.07-7.00(1H, m), 6.78 and 6.77 (1H, 2×d), 6.65 and 6.64 (1H, 2×d), 5.03-4.95(1H, m), 4.78 and 4.72 (1H, 2×t), 3.23-3.11 (2H, m), 2.90-2.78 (1H, m),2.30 (3H, s), 2.26-2.14 (1H, m), 2.12 and 2.06 (3H, 2×s), 0.86 (3H, d),0.72-0.63 (2H, m), 0.59-0.50 (2H, m).

Example 274

N-Cyclopropyl-3-[3-[[(1R,2R)-3-hydroxy-1-(2-methoxyphenyl)-2-methylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

a)N-[(1R,2R)-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-1-(2-methoxyphenyl)-2-methylpropyl]-2-methyl-2-propanesulfinamide

The title compound was prepared from(2S)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-N-methoxy-N,2-dimethyl-propanamide(Example 136a) and 2-methoxyphenylmagnesium bromide using methodsdescribed in the Example 136b.

¹H NMR δ (CDCl₃) 7.62-7.58 (2H, m), 7.53-7.49 (2H, m), 7.41-7.25 (6H,m), 7.20-7.16 (2H, m), 6.88 (1H, dt), 6.82 (1H, d), 4.58 (1H, dd), 4.34(1H, d), 3.76 (3H, s), 3.45 (1H, dd), 3.33 (1H, dd), 2.25-2.13 (1H, m),1.17 (9H, s), 1.03 (9H, s), 0.96 (3H, d).

b)3-[3-[[(1R,2R)-3-Hydroxy-2-methyl-1-(2-methoxyphenyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoicacid, methyl ester

The title compound was prepared fromN-[(1R,2R)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2-methyl-1-(2-methoxyphenyl)propyl]-2-methyl-2-propanesulfinamide(Example 274a) using the method described in the Example 136c.

¹H NMR δ (DMSO-d₆) 7.96 (1H, d), 7.85 and 7.80 (1H, s), 7.61-7.48 (2H,m), 7.30 (1H, d), 7.23 (1H, t), 7.01 (1H, d), 6.91 (1H, m), 6.79 (1H,d), 6.68 and 6.67 (1H, 2×d), 5.37 (1H, q), 4.63 (1H, q), 3.90-3.80 (6H,m), 3.29-3.12 (2H, m), 2.24-2.10 (1H, m), 2.16 and 2.09 (3H, 2×s), 0.86(3H, d).

c)N-Cyclopropyl-3-[3-[[(1R,2R)-3-hydroxy-1-(2-methoxyphenyl)-2-methylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

The title compound was prepared from3-[3-[[(1R,2R)-3-hydroxy-2-methyl-1-(2-methoxyphenyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoicacid, methyl ester (Example 274b) using the method described in theExample 136d.

MS: APCI(+ve) 463 (M+H⁺).

¹H NMR δ (DMSO-d₆) 8.44 and 8.38 (1H, 2×d), 7.86 (1H, m), 7.76 and 7.69(1H, 2×d), 7.56-7.45 (2H, m), 7.31 and 7.27 (1H, 2×dd), 7.23 (1H, m),7.03-6.99 (1H, m), 6.94-6.87 (1H, m), 6.80 and 6.80 (1H, 2×d), 6.67 and6.66 (1H, 2×d), 5.41-5.32 (1H, m), 4.67-4.59 (1H, m), 3.830 and 3.825(3H, 2×s), 3.27-3.22 (1H, m), 3.21-3.12 (1H, m), 2.90-2.78 (1H, m),2.25-2.14 (1H, m), 2.13 and 2.05 (3H, 2×s), 0.87 and 0.85 (3H, 2×d),0.72-0.63 (2H, m), 0.59-0.50 (2H, m).

Example 275

N-Cyclopropyl-3-[3-[[(1R,2S)-1-(2-methylphenyl)-2-methyl-3-(1-pyrrolidinyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

The title compound was prepared fromN-cyclopropyl-3-[3-[[(1R,2R)-3-hydroxy-1-(2-methylphenyl)-2-methylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide(Example 272) using methods described in the Example 138a and 138b.

MS: APCI(+ve) 500 (M+H⁺).

¹H NMR δ (DMSO-d₆) 8.57 and 8.39 (1H, 2×d), 8.45 and 8.37 (1H, 2×d),7.88-7.83 (1H, m), 7.74 and 7.67 (1H, 2×d), 7.48 (1H, t), 7.41 and 7.37(1H, 2×d), 7.22-7.08 (3H, m), 6.77 and 6.76 (1H, 2×d), 6.62 and 6.61(1H, 2×d), 5.34-5.26 (1H, m), 2.89-2.77 (1H, m), 2.48 (3H, s), 2.49-2.33(6H, m), 2.21-2.12 (1H, m), 2.11 and 2.02 (3H, 2×s), 1.75-1.64 (4H, m),0.85 and 0.84 (3H, 2×d), 0.72-0.63 (2H, m), 0.59-0.49 (2H, m).

Example 276

N-Cyclopropyl-3-[3-[[(1R,2S)-1-(3-methylphenyl)-2-methyl-3-(1-pyrrolidinyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

The title compound was prepared fromN-cyclopropyl-3-[3-[[(1R,2R)-3-hydroxy-1-(3-methylphenyl)-2-methylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide(Example 273) using methods described in the Example 138a and 138b.

MS: APCI(+ve) 500 (M+H⁺).

¹H NMR δ (DMSO-d₆) 9.11 and 8.93 (1H, 2×d), 8.45 and 8.41 (1H, 2×d),7.89-7.83 (1H, m), 7.74 and 7.69 (1H, 2×d), 7.48 and 7.47 (1H, 2×d),7.22 (1H, t), 7.14-7.02 (3H, m), 6.74 and 6.73 (1H, 2×d), 6.62 (1H, d),5.07-4.99 (1H, m), 2.89-2.79 (1H, m), 2.61-2.28 (6H, m), 2.31 (3H, s),2.11 and 2.05 (3H, s), 2.06-1.97 (1H, m), 1.82-1.65 (4H, m), 0.79 and0.78 (3H, 2×d), 0.73-0.64 (2H, m), 0.59-0.50 (2H, m).

Example 277

N-Cyclopropyl-3-[3-[[(1R,2S)-1-(2-methoxyphenyl)-2-methyl-3-(1-pyrrolidinyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

The title compound was prepared fromN-cyclopropyl-3-[3-[[(1R,2R)-3-hydroxy-1-(2-methoxyphenyl)-2-methylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide(Example 274) using methods described in the Example 138a and 138b.

MS: APCI(+ve) 516 (M+H±).

¹H NMR δ (DMSO-d₆) 8.49 and 8.31 (1H, 2×d), 8.45 and 8.40 (1H, 2×d),7.86 (1H, dt), 7.75 and 7.69 (1H, 2×d), 7.48 and 7.47 (1H, 2×d), 7.23(2H, t), 7.01 (1H, d), 6.93 (1H, t), 6.77 and 6.76 (1H, 2×d), 6.632 and6.628 (1H, 2×d), 5.59-5.50 (1H, m), 3.82 (3H, s), 2.90-2.78 (1H, m),2.59-2.31 (6H, m), 2.11 and 2.04 (3H, 2×s), 2.14-2.03 (1H, m), 1.79-1.61(4H, m), 0.78 (3H, d), 0.74-0.63 (2H, m), 0.60-0.49 (2H, m).

Example 278

N-Cyclopropyl-3-[3-[[1-[5-fluoro-2-[2-(methylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

a) 1-[5-Fluoro-2-(phenylmethoxy)phenyl]-cyclopropanamine

Ethylmagnesium bromide, (35.2 ml of a 3M solution in diethyl ether) wasadded as a slow stream to a mechanically stirred mixture oftetraisopropyl orthotitanate (16.37 mL) and2-(benzyloxy)-5-fluorobenzonitrile (12 g) in diethyl ether (400 mL)cooled to −78° C. The resulting solution was stirred at −78° C. for 15min and then warmed to room temperature over 1.5 h. Boron trifluorideetherate (13.38 mL) was added and the mixture was stirred for 30 min.The reaction was quenched with 1 M HCl (400 ml) and the aqueous layerwas separated. The diethyl ether layer was further extracted into 1M HCl(2×200 mL). The combined aqueous layers were cooled in an ice bath andbasified with 1M aqueous NaOH solution. The resulting precipitate wasfiltered through celite washing the pad extensively with water (200 mL),dichloromethane (4×200 mL) then dichloromethane/MeOH (90:10, 300 mL).The combined filtrates were separated and the aqueous layer furtherextracted into dichloromethane (2×200 mL). The combined organics weredried (MgSO₄) and evaporated and residue purified by SCX resin (elutingwith methanol followed by 10% 880 ammonia in methanol). The basicfractions were evaporated to give the subtitle compound (3.4g).

¹H NMR δ (CDCl₃) 7.49-7.44 (2H, m), 7.42-7.36 (2H, m), 7.36-7.29 (1H,m), 6.99-6.92 (1H, m), 6.88-6.82 (2H, m), 5.13 (2H, s), 2.13 (2H, s),1.00-0.95 (2H, m), 0.86-0.82 (2H, m).

b)3-[5-Bromo-3-[[1-[5-fluoro-2-(phenylmethoxy)phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoicacid methyl ester

A solution of 1-[5-fluoro-2-(phenylmethoxy)phenyl]-cyclopropanamine(Example 278a, 1.7g) in dioxane (200 mL) was treated with3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methylester (Example 1b, 1.99 g) and N-ethyldiisopropylamine (1.7 ml,) undernitrogen. The resulting solution was stirred at 100° C. for 8 h. Thecooled reaction mixture was diluted with 2M HCl (300 mL), and extractedwith diethyl ether (3×300 mL). The combined organics were dried (MgSO₄)filtered and evaporated to afford crude product. Trituration withiso-hexane gave the subtitle compound (2.89g).

¹H NMR δ (DMSO-d₆) 7.98-7.91 (1H, m), 7.87 (1H, s), 7.62 (1H, s),7.56-7.24 (6H, m), 7.05-6.98 (3H, m), 3.85 (3H, s), 3.58-3.55 (2H, m),2.13 (3H, s), 1.32-1.05 (4H, m).

c)3-[3-[[1-(5-fluoro-2-hydroxyphenyl)cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoicacid methyl ester

To3-[5-bromo-3-[[1-[5-fluoro-2-(phenylmethoxy)phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoicacid, methyl ester (Example 278b, 2.8 g) in ethanol (200 mL) was addedammonium formate (5.0 g) and 10% Pd/C (1.0 g). The reaction was heatedat 75° C. for 1 h, filtered through celite washing the celite with warmethanol (100 mL) followed by dichloromethane (2000 mL). The combinedfiltrates were evaporated, diluted with dichloromethane (1000 mL) andwashed with water, dried (MgSO₄) and evaporated to give the subtitlecompound (1.2 g)

¹H NMR δ (DMSO-d₆) 11.12 (1H, s), 8.43 (1H, s), 7.96 (1H, dd), 7.85 (1H,d), 7.56 (1H, d), 7.23 (1H, dd), 6.98-6.91 (1H, m), 6.83 (2H, dd),6.77-6.72 (1H, m), 3.84 (3H, s), 2.12 (3H, s), 1.28-1.24 (2H, m),1.18-1.07 (2H, m).

d)N-cyclopropyl-3-[3-[[1-(5-fluoro-2-hydroxyphenyl)cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

Isopropylmagnesium chloride (5.86 mL of a 2M solution in THF) was addedover 20 min to a solution of cyclopropylamine (2.066 mL) and3-[3-[[1-(5-fluoro-2-hydroxyphenyl)cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoicacid methyl ester (Example 278c, 1.2 g) in THF (200 mL) at roomtemperature under nitrogen. The reaction mixture was stirred for 1 h.Water and 2M HCl were cautiously added and the aqueous layer extractedwith dichloromethane (3×200 mL), dried (MgSO₄) and the solvent removedto give the subtitle compound (1.22g)

1H NMR δ (DMSO-d₆) 8.58-8.48 (1H, m), 8.41-8.35 (1H, m), 7.86 (1H, d),7.72 (1H, s), 7.48 (1H, d), 7.28-7.21 (1H, m), 7.05-6.86 (2H, m),6.83-6.72 (2H, m), 3.65-3.57 (2H, m), 2.89-2.78 (1H, m), 2.10 (3H, s),1.80-1.72 (2H, m), 0.73-0.63 (2H, m), 0.58-0.49 (2H, m).

e)3-[3-[[1-[2-(2-chloroethoxy)-5-fluorophenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide

N-Cyclopropyl-3-[3-[[1-(5-fluoro-2-hydroxyphenyl)cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide(Example 278d 1.22 g), 1-bromo-2-chloroethane (2.4 mL) and cesiumcarbonate (9.15 g) were stirred together in acetonitrile (100 mL) at 80°C. under nitrogen for 16 h. The cooled reaction mixture was evaporatedto dryness, diluted with water (200 mL) and extracted withdichloromethane (3×100 mL). The combined organics were dried (MgSO₄),filtered and evaporated. The residue was triturated with 1:1 iso-hexane:diethyl ether to give the subtitle compound (1.13 g)

¹H NMR δ (DMSO-d₆) 8.37 (1H, d), 7.84 (1H, dd), 7.69 (1H, d), 7.46 (1H,d), 7.33-7.27 (2H, m), 7.08-6.95 (2H, m), 6.89 (1H, d), 6.73 (1H, d),4.29 (2H, t), 3.99 (2H, t), 2.89-2.76 (1H, m), 2.06 (3H, s), 0.71-0.60(2H, m), 0.57-0.48 (2H, m).

f)N-Cyclopropyl-3-[3-[[1-[5-fluoro-2-[2-(methylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

3-[3-[[1-[2-(2-chloroethoxy)-5-fluorophenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide(Example 278e, 0.25g) and 40% methylamine in water (1 mL) were stirredtogether at 100° C. in dioxane (8 mL) in a sealed tube for 24 h.Purification of the cooled solution by preparative HPLC (Xbridge column—acetonitrile/0.2% ammonia mobile phase) gave the title compound (110mg).

MS: APCI(+ve) 492 (M+H)⁺.

¹H NMR δ (DMSO-d₆) 8.37 (1H, d), 7.85 (1H, d), 7.69 (1H, s), 7.58 (1H,s), 7.46 (1H, d), 7.30 (1H, dd), 7.06-6.91 (2H, m), 6.88 (1H, d), 6.71(1H, d), 4.03 (2H, t), 2.90-2.79 (3H, m), 2.34 (3H, s), 2.06 (3H, s),1.25-1.06 (4H, m), 0.70-0.62 (2H, m), 0.57-0.50 (2H, m)

The following examples 279-280 were prepared in a similar manner toExample 278:

Example 279

N-Cyclopropyl-3-[3-[[1-[5-fluoro-2-[2-[(2-hydroxyethyl)amino]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

MS: APCI(+ve) 522 (M+H)⁺.

¹H NMR δ (DMSO-d₆) 8.37 (1H, d), 7.85 (1H, dd), 7.69 (1H, d), 7.49 (1H,s), 7.46 (1H, d), 7.29 (1H, dd), 7.05-6.93 (2H, m), 6.89 (1H, d), 6.72(1H, d), 4.45-4.40 (1H, m), 4.03 (2H, t), 3.46 (2H, q), 2.94 (2H, t),2.88-2.78 (1H, m), 2.67 (2H, t), 2.06 (3H, s), 1.26-1.07 (4H, m),0.71-0.62 (2H, m), 0.56-0.49 (2H, m).

Example 280

N-Cyclopropyl-3-[3-[[1-[2-[2-(ethylamino)ethoxy]-5-fluorophenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide

MS: APCI(+ve) 506 (M+H)⁺.

¹H NMR δ (DMSO-d₆) 8.37 (1H, d), 7.85 (1H, dd), 7.69 (1H, d), 7.52 (1H,s), 7.46 (1H, d), 7.29 (1H, dd), 7.05-6.93 (2H, m), 6.88 (1H, d), 6.72(1H, d), 4.03 (2H, t), 2.92 (2H, t), 2.88-2.79 (1H, m), 2.61 (2H, q),2.06 (3H, s), 1.26-1.06 (4H, m), 0.99 (3H, t), 0.70-0.63 (2H, m),0.55-0.49 (2H, m)

Example 281

N-Cyclopropyl-3-fluoro-5-{3-[(1-{5-fluoro-2-[2-(methylamino)ethoxy]phenyl}cyclopropyl)amino]-2-oxopyrazin-1(2H)-yl}-4-methylbenzamide

a) Methyl3-[3-({1-[2-(benzyloxy)-5-fluorophenyl]cyclopropyl}amino)-5-bromo-2-oxopyrazin-1(2H)-yl]-5-fluoro-4-methylbenzoate

The subtitle compound was prepared from1-(2-(benzyloxy)-5-fluorophenyl)cyclopropanamine (Example 278a) andmethyl 3-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-5-fluoro-4-methylbenzoate(Example 252g) using a similar method to that described for Example268d.

¹H NMR δ (DMSO-d₆) 7.83-7.76 (2H, m), 7.66-7.63 (1H, m), 7.55-7.49 (2H,m), 7.41-7.28 (4H, m), 7.08-7.00 (3H, m), 5.20 (2H, s), 3.85 (3H, s),2.04 (3H, s), 1.29-1.10 (4H, m).

b)N-Cyclopropyl-3-fluoro-5-[3-{[1-(5-fluoro-2-hydroxyphenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide

The subtitle compound was prepared from methyl3-[3-({1-[2-(benzyloxy)-5-fluorophenyl]cyclopropyl}amino)-5-bromo-2-oxopyrazin-1(2H)-yl]-5-fluoro-4-methylbenzoate(Example 281a) using similar methods to that described for Example 259band 259c.

¹H NMR δ (DMSO-d₆) 8.58 (1H, s), 8.48 (1H, d), 7.75 (1H, d), 7.65 (1H,s), 7.24 (1H, dd), 6.99-6.73 (4H, m), 2.90-2.77 (1H, m), 2.00 (3H, s),1.31-1.13 (4H, m), 0.75-0.63 (2H, m), 0.59-0.50 (2H, m).

c)3-[3-({1-[2-(2-Chloroethoxy)-5-fluorophenyl]cyclopropyl}amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide

The subtitle compound was prepared fromN-cyclopropyl-3-fluoro-5-[3-{[1-(5-fluoro-2-hydroxyphenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide(Example 281 b) using a similar method to that described for Example259d.

¹H NMR δ (DMSO-d₆) 8.46 (1H, d), 7.73 (1H, d), 7.61 (1H, s), 7.35-7.26(2H, m), 7.10-6.94 (2H, m), 6.90 (1H, d), 6.77 (1H, d), 4.32-4.24 (2H,m), 4.02-3.94 (2H, m), 2.88-2.78 (1H, m), 1.96 (3H, s), 1.41-1.09 (4H,m), 0.76-0.46 (4H, m)

d)N-Cyclopropyl-3-fluoro-5-{3-[(1-{5-fluoro-2-[2-(methylamino)ethoxy]phenyl}cyclopropyl)amino]-2-oxopyrazin-1(2H)-yl}-4-methylbenzamide

The title compound was prepared from3-[3-({1-[2-(2-chloroethoxy)-5-fluorophenyl]cyclopropyl}amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide(Example 281c) using a similar method to that described for Example259e.

MS: APCI(+ve) 510.2 (M+H)⁺.

¹H NMR δ (DMSO-d₆) 8.47 (1H, d), 7.73 (1H, d), 7.65-7.61 (2H, m), 7.30(1H, dd), 7.06-6.92 (2H, m), 6.90 (1H, d), 6.75 (1H, d), 4.03 (2H, t),2.91-2.77 (3H, m), 2.35 (3H, s), 1.97 (3H, d), 1.28-1.05 (4H, m),0.73-0.64 (2H, m), 0.59-0.47 (2H, m).

Example 282

N-Cyclopropyl-3-fluoro-5-[3-{[1-(5-fluoro-2-{2-[(2-hydroxyethyl)amino]ethoxy}phenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide

The title compound was prepared from3-[3-({1-[2-(2-chloroethoxy)-5-fluorophenyl]cyclopropyl}amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide(Example 281c) and ethanolamine using a similar method to that describedfor Example 167f.

MS: APCI(+ve) 540 (M+H)+.

¹H NMR δ (DMSO-d₆) 8.46 (1H, d), 7.73 (1H, d), 7.61 (1H, s), 7.53 (1H,s), 7.29 (1H, dd), 7.06-6.92 (2H, m), 6.90 (1H, d), 6.76 (1H, d), 4.42(1H, t), 4.03 (2H, t), 3.46 (2H, q), 2.94 (2H, t), 2.89-2.78 (1H, m),2.67 (2H, t), 1.97 (3H, d), 1.28-1.04 (4H, m), 0.72-0.61 (2H, m),0.58-0.45 (2H, m)

Example 283

N-Cyclopropyl-3-[3-({1-[3-fluoro-2-(2-{[(2R)-2-hydroxypropyl]amino}ethoxy)phenyl]cyclopropyl}amino)-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide

a) 2-(Benzyloxy)-3-fluorobenzonitrile

Benzyl alcohol (5.51 mL) was added dropwise over 20 min to a stirredsuspension of sodium hydride (2.128 g of a 60% dispersion in mineraloil) and 2,3-difluorobenzonitrile (7.4 g) in THF (100 mL) with externalice bath cooling to maintain temperature around 25° C. After additionwas complete, the reaction mixture was stirred at room temperature for24 h, quenched with water (200 mL) and extracted into ethyl acetate(3×120 mL), combined organics were dried (MgSO₄) and evaporated. Theresidual oil was purified (SiO₂ chromatography eluting with 20% ether inisohexane) to give the subtitle compound as an oil (9.70 g).

¹H NMR δ (CDCl₃) 7.54-7.44 (2H, m), 7.40-7.26 (5H, m), 7.10-7.01 (1H,m), 5.33 (2H, s)

b) 1-[2-(Benzyloxy)-3-fluorophenyl]cyclopropanamine

A solution of ethylmagnesium bromide, 3M in diethyl ether (28.2 mL) wasadded as a slow is stream to a mechanically stirred mixture oftetraisopropyl orthotitanate (13.09 mL,) and2-(benzyloxy)-3-fluorobenzonitrile (Example 283a, 9.6 g) in diethylether (400 mL) cooled to −78° C. The resulting solution was stirred at−78° C. for 15 min and then warmed to room temperature over 1 h 30 min.An ice bath was placed around the reaction and boron trifluorideetherate (10.71 mL) was added as a slow stream (caution exothermic) andthe mixture was stirred for 30 min. The reaction was cooled (ice bath)and quenched with 1 M aqueous HCl (400 mL added portionwise). Theaqueous layer was separated and the diethyl ether layer furtherextracted into 1M HCl (2×200 mL) (ethyl acetate added to the diethylether to aid solubility). The aqueous layer was cooled in an ice bathand basified with stirring with a 10M aqueous NaOH solution. Theresulting precipitate was filtered through Celite, washing the pad withwater (200 mL) then DCM (4×200 mL) then DCM/MeOH (90:10, 300 mL). Thecombined filtrates were separated and the aqueous layer furtherextracted with DCM (2×200 mL). The combined organics were dried (MgSO₄)and evaporated, the residue was purified on SCX resin (50 g) elutingwith DCM, methanol (discarded) and flushing with 20% ammonia in methanolto give the subtitle compound as an oil (2.54 g).

¹H NMR δ (CDCl₃) 7.54-7.50 (1H, m), 7.43-7.31 (2H, m), 7.06-6.89 (5H,m), 5.22 (2H, s), 0.96-0.93 (2H, m), 0.84-0.80 (2H, m).

c) Methyl3-[3-({1-[2-(benzyloxy)-3-fluorophenyl]cyclopropyl}amino)-5-bromo-2-oxopyrazin-1(2H)-yl]-4-methylbenzoate

Prepared using a similar method to Example 252h from1-(2-(benzyloxy)-3-fluorophenyl)cyclopropanamine (Example 283b) andmethyl 3-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-4-methylbenzoate (Example252g).

¹H NMR δ (DMSO-d₆) 7.94 (1H, dd), 7.86 (1H, d), 7.72 (1H, s), 7.58-7.51(3H, m), 7.44-7.32 (5H, m), 7.23-7.16 (1H, m), 7.11-7.03 (1H, m), 5.19(2H, s), 3.83 (3H, s), 2.11 (3H, s), 1.26-1.14 (4H, m)

d) Methyl3-[3-{[1-(3-fluoro-2-hydroxyphenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzoate

Prepared using a similar method to Example 252j from methyl3-[3-({1-[2-(benzyloxy)-3-fluorophenyl]cyclopropyl]amino)-5-bromo-2-oxopyrazin-1(2H)-yl]-4-methylbenzoate(Example 283c).

¹H NMR δ (DMSO-d₆)) 8.63 (1H, s), 7.96 (1H, dd), 7.86 (1H, d), 7.56 (1H,d), 7.27 (1H, d), 7.09-7.02 (1H, m), 6.90 (1H, d), 6.80 (1H, d),6.79-6.74 (1H, m), 3.84 (3H, s), 2.13 (3H, s), 1.32-1.26 (2H, m),1.12-1.09 (2H, m)

e)N-Cyclopropyl-3-[3-([1-(3-fluoro-2-hydroxyphenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide

The subtitle compound was prepared from methyl3-[3-{[1-(3-fluoro-2-hydroxyphenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzoate(Example 283d) using a similar method to that described for Example 252i

¹H NMR δ (DMSO-d₆) 8.75 (1H, s), 8.39 (1H, d), 7.85 (1H, dd), 7.73 (1H,d), 7.47 (1H, d), 7.28 (1H, d), 7.10-7.03 (1H, m), 6.92 (1H, d), 6.82(1H, d), 6.80-6.74 (1H, m), 2.88-2.79 (1H, m), 2.10 (3H, s), 1.32-1.09(4H, m), 0.72-0.65 (2H, m), 0.58-0.50 (2H, m)

f)3-[3-({1-[2-(2-Chloroethoxy)-3-fluorophenyl]cyclopropyl}amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-4-methylbenzamide

The subtitle compound was prepared fromN-cyclopropyl-3-[3-{[1-(3-fluoro-2-hydroxyphenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide(Example 283e) using a similar method to that described for Example259d.

¹H NMR δ (DMSO-d₆) 8.41-8.36 (1H, m), 7.88-7.82 (1H, m), 7.71-7.67 (1H,m), 7.51-7.38 (2H, m), 7.24-6.99 (2H, m), 6.87-6.82 (1H, m), 6.74-6.70(1H, m), 4.40-4.32 (2H, m), 4.07-4.00 (2H, m), 2.89-2.78 (1H, m), 2.07(3H, s), 1.29-1.16 (4H, m), 0.71-0.63 (2H, m), 0.57-0.51 (2H, m)

g)N-cyclopropyl-3-[3-({1-[3-fluoro-2-(2-{[(2R)-2-hydroxypropyl]amino}ethoxy)phenyl]cyclopropyl}amino)-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide

3-[3-({1-[2-(2-chloroethoxy)-3-fluorophenyl]cyclopropyl}amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-4-methylbenzamide(Example 283f) (0.3g) and 2-aminoethanol (0.147 g) were stirred togetherat 100° C. in dioxane (8 mL) in a sealed tube for 24 h. Purification bypreparative HPLC (Xterra column 0.2% ammonia/MeCN eluent) give the titlecompound (0.094 g).

MS: APCI(+ve) 536 (M+H)⁺.

¹H NMR δ (DMSO-d₆) 8.38 (1H, s), 8.30 (1H, d), 7.85 (1H, d), 7.69 (1H,s), 7.49-7.35 (2H, m), 7.14 (1H, t), 7.07-6.94 (1H, m), 6.89-6.83 (1H,m), 6.73-6.67 (1H, m), 4.49-4.42 (1H, m), 4.19-4.03 (2H, m), 3.80-3.66(1H, m), 3.33 (2H, s), 2.95 (2H, s), 2.88-2.78 (1H, m), 2.58-2.54 (1H,m), 2.06 (3H, s), 1.32-1.08 (2H, m), 1.07-0.99 (2H, m), 0.89-0.78 (2H,m), 0.70-0.64 (2H, m), 0.58-0.48 (2H, m).

The following Examples 284-287 (Table 12) were prepared using a similarmethod to that described for Example 283:

Example 284

3-[3-({1-[2-(2-Aminoethoxy)-3-fluorophenyl]cyclopropyl]amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-4-methylbenzamide

Example 285

N-Cyclopropyl-3-[3-{[1-(3-fluoro-2-{2-[(2-hydroxyethyl)amino]ethoxy]phenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide

Example 286

N-Cyclopropyl-3-{3-[(1-{2-[2-(ethylamino)ethoxy]-3-fluorophenyl}cyclopropyl)amino]-2-oxopyrazin-1(2H)-yl}-4-methylbenzamide

Example 287

N-Cyclopropyl-3-{3-[(1-{3-fluoro-2-[2-(methylamino)ethoxy]phenyl}cyclopropyl)amino]-2-oxopyrazin-1(2H)-yl}-4-methylbenzamide

TABLE 12

MS [M + H]⁺ Example R m/z ¹H NMR δ (DMSO-d₆) 284

478 8.54-8.30 (2H, m), 7.84 (1H, d), 7.69 (1H, s), 7.45 (1H, d), 7.39(1H, d), 7.12 (1H, t), 6.99 (1H, q), 6.85 (1H, d), 6.69 (1H, d), 4.07-3.99 (2H, m), 2.96 (2H, t), 2.88-2.77 (1H, m), 2.06 (3H, s), 1.27-1.06(4H, m), 0.73- 0.46 (4H, m) 285

522 8.38 (2H, s), 7.88-7.81 (1H, m), 7.71-7.67 (1H, m), 7.50-7.37 (2H,m), 7.20-7.08 (1H, m), 7.05-6.96 (1H, m), 6.86 (1H, t), 6.70 (1H, t),4.49-4.41 (1H, m), 4.16-4.06 (2H, m), 3.55-3.45 (2H, m), 3.00-2.90 (2H,m), 2.88-2.79 (1H, m), 2.76-2.65 (2H, m), 2.06 (3H, d), 1.29-1.04 (4H,m), 0.75-0.59 (2H, m), 0.58-0.50 (2H, m) 286

506 8.45-8.34 (2H, m), 7.85 (1H, d), 7.69 (1H, s), 7.46 (1H, d), 7.39(1H, d), 7.13 (1H, t), 7.06-6.95 (1H, m), 6.84 (1H, d), 6.69 (1H, d),4.17-4.02 (2H, m), 2.97-2.88 (2H, m), 2.86-2.81 (1H, m), 2.73-2.58 (2H,m), 2.06 (3H, s), 1.28-1.10 (4H, m), 1.09-0.99 (3H, m), 0.74-0.61 (2H,m), 0.56-0.48 (2H, m) 287

492 8.45 (1H, s), 8.37 (1H, d), 7.84 (1H, d), 7.68 (1H, s), 7.46 (1H,d), 7.39 (1H, d), 7.12 (1H, t), 7.04-6.93 (1H, m), 6.85 (1H, d), 6.68(1H, d), 4.18-4.02 (2H, m), 2.95-2.78 (2H, m), 2.38 (3H, s), 2.06 (3H,s), 1.26-1.07 (4H, m), 0.70-0.63 (2H, m), 0.57-0.50 (2H, m)

Example 288

N-Cyclopropyl-4-ethyl-3-{3-[(1-methyl-1-{2-[2-(methylamino)ethoxy]phenyl}ethyl)amino]-2-oxopyrazin-1(2H)-yl}benzamide

a) Methyl 3-[(cyanomethyl)amino]-4-ethylbenzoate

To a stirred solution of methyl 3-amino-4-ethylbenzoate (6.10 g) in THF(56.7 mL) at room temperature was added Hunig's Base (11.89 mL) followedby bromoacetonitrile (4.74 mL). The mixture was heated at reflux for 16h. The reaction was cooled to room temperature and concentrated invacuo. 1N aqueous HCl and DCM were added. The organic layer wasseparated, dried (MgSO₄) and concentrated to give the subtitle compoundas an oil (7.46 g).

¹H NMR δ (DMSO-d₆) 7.35 (d, 1H), 7.24-7.18 (m, 2H), 5.97 (t, 1H), 4.34(d, 2H), 3.84 (d, 2H), 3.32 (d, 3H), 1.15 (t, 3H)

b) Methyl 3-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-4-ethylbenzoate

The subtitle compound was prepared from methyl3-[(cyanomethyl)amino]-4-ethylbenzoate (Example 288a) using a similarmethod to that described for Example 252g.

¹H NMR δ (DMSO-d₆) 8.14 (d, 1H), 8.06 (s, 2H), 8.04-8.02 (m, 1H), 3.87(s, 3H), 1.11 (t, 3H) Other resonances obscured under solvent peak (2.4ppm)

c) Methyl3-[3-({1-[2-(benzyloxy)phenyl]-1-methylethyl}amino)-5-bromo-2-oxopyrazin-1(2H)-yl]-4-ethylbenzoate

The subtitle compound was prepared from methyl3-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-4-ethylbenzoate (Example 288b) andα,α-dimethyl-2-(phenylmethoxy)-benzenemethanamine (Example 198d) using asimilar method to that described for Example 252h.

MS: APCI(+ve) 576 (M+H)⁺.

d) 3-[3-({1-(Benzyloxy)phenyl]-1-methylethyl}amino)-5-bromo-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-4-ethylbenzamide

The subtitle compound was prepared from methyl3-[3-({1-[2-(benzyloxy)phenyl]-1-methylethyl}amino)-5-bromo-2-oxopyrazin-1(2H)-yl]-4-ethylbenzoate(Example 288c) using a similar method to that described for Example252i.

MS: APCI(+ve) 601 (M+H)⁺.

¹H NMR δ (DMSO-d₆) 8.42 (d, 1H), 7.91 (dd, 1H), 7.73 (d, 1H), 7.45-7.21(m, 9H), 7.10 (t, 2H), 6.96 (t, 1H), 5.12 (s, 2H), 2.90-2.82 (m, 1H),2.39 (q, 2H), 1.84 (d, 6H), 1.06 (t, 3H), 0.74-0.67 (m, 2H), 0.58-0.53(m, 2H)

e)N-Cyclopropyl-4-ethyl-3-[3-{[1-(2-hydroxyphenyl)-1-methylethyl]amino}-2-oxopyrazin-1(2H)-yl]benzamide

The subtitle compound was prepared from3-[3-({1-[2-(benzyloxy)phenyl]-1-methylethyl}amino)-5-bromo-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-4-ethylbenzamide(Example 288d) using a similar method to that described for Example252j.

MS: APCI(+ve) 433 (M+H)⁺.

f)3-[3-({1-[2-(2-Chloroethoxy)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-4-ethylbenzamide

The subtitle compound was prepared fromN-cyclopropyl-4-ethyl-3-[3-{[1-(2-hydroxyphenyl)-1-methylethyl]amino}-2-oxopyrazin-1(2H)-yl]benzamide(Example 288e) using a similar method to that described for Example252k.

MS: APCI(+ve) 495 (M+1-1)′.

¹H NMR δ (DMSO-d₆) 8.43 (d, 1H), 7.91 (dd, 1H), 7.71 (d, 1H), 7.52 (d,1H), 7.34 (dd, 1H), 7.21 (t, 1H), 6.97-6.91 (m, 3H), 6.65 (q, 2H),4.26-4.13 (m, 2H), 3.93 (t, 2H), 2.89-2.81 (m, 1H), 2.45-2.38 (m, 2H),1.87 (s, 3H), 1.84 (s, 3H), 1.06 (t, 3H), 0.70-0.67 (m, 2H), 0.57-0.54(m, 2H)

g)N-Cyclopropyl-4-ethyl-3-{3-[(1-methyl-1-{2-[2-(methylamino)ethoxy]phenyl}ethyl)amino]-2-oxopyrazin-1(2H)-yl}benzamide

The title compound was prepared from3-[3-({1-[2-(2-chloroethoxy)phenyl]-1-methylethyl]amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-4-ethylbenzamide(Example 288f) using a similar method to that described for Example252l.

MS: APCI(+ve) 490.4 (M+H)⁺.

¹H NMR δ (DMSO-d₆) 8.43 (d, 1H), 7.91 (dd, 1H), 7.69 (d, 1H), 7.51 (d,1H), 7.34 (d, 1H), 7.20 (t, 1H), 6.98-6.88 (m, 3H), 6.67-6.62 (m, 2H),4.02-3.88 (m, 2H), 2.90-2.80 (m, 3H), 2.45-2.35 (m, 2H), 2.26 (s, 3H),1.82 (s, 6H), 1.06 (t, 3H), 0.70-0.66 (m, 2H), 0.55-0.53 (m, 2H).

The following Examples 289 to 292 (Table 13) were prepared using asimilar method to that described for Example 288 from3-[3-({1-[2-(2-chloroethoxy)phenyl]-1-methylethyl]amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-4-ethylbenzamide(Example 288f) and suitable amine.

Example 289

N-Cyclopropyl-4-ethyl-3-[3-({1-[2-(2-{[(2S)-2-hydroxypropyl]amino]ethoxy)phenyl]-1-methylethyl]amino)-2-oxopyrazin-1(2H)-yl}benzamide

Example 290

N-Cyclopropyl-4-ethyl-3-{3-[(1-{2-[2-(ethylamino)ethoxy]phenyl]-1-methylethyl]amino]-2-oxopyrazin-1(2H)-yl}benzamide

Example 291

N-Cyclopropyl-4-ethyl-3-[3-{[1-(2-{2-[(2-hydroxyethyl)amino]ethoxy]phenyl)-1-methylethyl]amino}-2-oxopyrazin-1(2H)-yl]benzamide

Example 292

3-[3-({1-[2-(2-Aminoethoxy)phenyl]-1-methylethyl]amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-4-ethylbenzamide

TABLE 13

MS [M + H]⁺ Example R m/z ¹H NMR δ (DMSO-d₆) 289

534 8.44 (s, 1H), 7.91 (d, 1H), 7.71 (s, 1H), 7.51 (d, 1H), 7.33 (d,1H), 7.22-7.17 (m, 1H), 6.98-6.90 (m, 3H), 6.65 (d, 2H), 4.38 (s, 1H),3.98-3.94 (m, 2H), 3.61 (s, 1H), 2.95- 2.81 (m, 4H), 2.45 (d, 2H), 1.84(s, 6H), 1.06 (d, 3H), 1.00 (d, 3H), 0.69 (d, 2H), 0.56 (s, 2H) 290

504 8.43 (d, 1H), 7.91 (d, 1H), 7.70 (d, 1H), 7.51 (d, 1H), 7.34 (d,1H), 7.19 (t, 1H), 6.98- 6.88 (m, 3H), 6.65 (q, 2H), 4.02-3.89 (m, 2H),2.91-2.82 (m, 3H), 2.54-2.51 (m, 2H), 2.45-2.35 (m, 2H), 1.84 (s, 3H),1.83 (s, 3H), 1.06 (t, 3H), 0.90 (t, 3H), 0.70- 0.66 (m, 2H), 0.56-0.54(m, 2H) 291

  520.4 8.43 (d, 1H), 7.91 (dd, 1H), 7.70 (d, 1H), 7.51 (d, 1H), 7.33(dd, 1H), 7.19 (t, 1H), 6.98-6.87 (m, 3H), 6.64 (q, 2H), 4.38 (t, 1H),4.01-3.90 (m, 2H), 3.39 (q, 2H), 2.94- 2.81 (m, 3H), 2.59 (t, 2H),2.45-2.34 (m, 2H), 1.84 (s, 3H), 1.82 (s, 3H), 1.06 (t, 3H), 0.70-0.67(m, 2H), 0.56-0.54 (m, 2H) 292

476 8.44 (d, 1H), 7.90 (dd, 1H), 7.69 (d, 1H), 7.51 (d, 1H), 7.34 (d,1H), 7.19 (t, 1H), 6.97- 6.88 (m, 3H), 6.67-6.62 (m, 2H), 3.91- 3.84 (m,2H), 2.89-2.83 (m, 3H), 2.42- 2.38 (m, 2H), 1.84 (s, 3H), 1.83 (s, 3H),1.06 (t, 3H), 0.70-0.66 (m, 2H), 0.57-0.54 (m, 2H)

The following Examples 293 to 298 (Table 14) were prepared using asimilar method to that described for Example 230 using3-(3-(1-(2-(2-chloroethoxy)phenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-4-methylbenzamide(Example 167e) and a suitable amine.

Example 293

N-Cyclopropyl-3-[3-({1-[2-(2-{[(1R)-1-(hydroxymethyl)-2-methylpropyl]amino]ethoxy)phenyl]cyclopropyl]amino)-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide

Example 294

N-Cyclopropyl-3-[3-({1-[2-(2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino]ethoxy)phenyl]cyclopropyl]amino)-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide

Example 295

N-Cyclopropyl-3-[3-{[1-(2-{2-[(1,1-dioxidotetrahydrothiophen-3-yl)amino]ethoxy]phenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide

Example 296

N-Cyclopropyl-3-{3-[(1-{2-[2-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethoxy]phenyl}cyclopropyl)amino]-2-oxopyrazin-1(2H)-yl}-4-methylbenzamide

Example 297

N-Cyclopropyl-4-methyl-3-{3-[(1-{2-[2-(1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethoxy]phenyl}cyclopropyl)amino]-2-oxopyrazin-1(2H)-yl}benzamide

Example 298

N-Cyclopropyl-4-methyl-3-{2-oxo-3-[(1-{2-[2-(propylamino)ethoxy]phenyl}cyclopropyl)amino]pyrazin-1(2H)-yl}benzamide

TABLE 14

MS [M + H]⁺ Example R m/z ¹H NMR δ (DMSO-d₆) 293

546 8.02 (d, 1H), 7.81 (s, 1H), 7.77 (d, 1H), 7.64 (d, 1H), 7.40 (t,1H), 7.14 (d, 1H), 7.11- 7.04 (m, 2H), 6.75 (s, 1H), 4.38-4.31 (m, 2H),3.92-3.84 (m, 1H), 3.72-3.64 (m, 2H), 3.51 (s, 2H), 3.35-3.26 (m, 2H),3.04- 2.97 (m, 1H), 2.73-2.66 (m, 1H), 2.31 (s, 3H), 2.11-2.01 (m, 1H),1.52-1.26 (m, 4H), 1.21-1.07 (m, 6H), 0.97 (d, 2H), 0.82- 0.75 (m, 2H).294

534 8.37-8.32 (m, 1H), 7.87-7.81 (m, 1H), 7.69-7.65 (m, 1H), 7.54-7.42(m, 2H), 7.39-7.34 (m, 1H), 7.23-7.14 (m, 1H), 6.98-6.92 (m, 1H),6.89-6.81 (m, 2H), 6.72-6.66 (m, 1H), 4.43-4.34 (m, 2H), 4.10-4.02 (m,2H), 3.05-2.96 (m, 2H), 2.86-2.79 (m, 1H), 2.65-2.58 (m, 1H), 2.22-2.10(m, 5H), 1.25-1.13 (m, 4H), 1.12-0.99 (m, 2H), 0.70-0.62 (m, 2H),0.56-0.49 (m, 2H). 295

578 7.81 (d, 1H), 7.61 (d, 1H), 7.49 (d, 1H), 7.44 (d, 1H), 7.18 (t,1H), 6.92 (d, 1H), 6.88- 6.82 (m, 2H), 6.60-6.55 (m, 1H), 4.16- 4.07 (m,2H), 3.64-3.54 (m, 1H), 3.46 (q, 2H), 3.16-2.97 (m, 3H), 2.95-2.84 (m,2H), 2.83-2.75 (m, 1H), 2.39-2.24 (m, 1H), 2.11 (d, 2H), 2.05-1.86 (m,1H), 1.39- 1.20 (m, 3H), 1.15 (t, 3H), 1.10-0.96 (m, 1H), 0.79-0.71 (m,2H), 0.63-0.55 (m, 2H). 296

566 8.35 (d, 1H), 7.84 (dd, 1H), 7.68 (d, 1H), 7.48 (dd, 1H), 7.46 (d,1H), 7.28 (s, 1H), 7.21 (td, 1H), 7.00 (d, 1H), 6.99 (d, 1H), 6.89-6.85(m, 2H), 6.81 (d, 1H), 6.70 (d, 1H), 4.22 (t, 2H), 3.95 (t, 2H), 3.79(d, 1H), 3.75 (d, 1H), 3.01 (d, 4H), 2.87-2.78 (m, 1H), 2.05 (s, 3H),1.25-1.03 (m, 4H), 0.69- 0.64 (m, 2H), 0.54-0.50 (m, 2H) 297

580 8.35 (d, 1H), 7.84 (dd, 1H), 7.68 (d, 1H), 7.47 (m, 2H), 7.36 (s,1H), 7.25 (s, 1H), 7.20 (dt, 1H), 7.00 (d, 1H), 6.86 (dt, 1H), 6.86 (d,1H), 6.70 (d, 1H), 4.19 (t, 2H), 3.52 (s, 2H), 3.44 (s, 3H), 2.98 (t,2H), 2.88 (t, 2H), 2.85-2.79 (m, 1H), 2.56 (t, 2H), 2.05 (s, 3H),1.27-1.03 (m, 4H), 0.69-0.63 (m, 2H), 0.55-0.49 (m, 2H). 298

502 d 7.81 (d, 1H), 7.61 (s, 1H), 7.53 (d, 1H), 7.43 (d, 1H), 7.19 (t,1H), 6.92 (d, 1H), 6.89- 6.83 (m, 2H), 6.57 (d, 1H), 4.14 (t, 2H),3.09-3.01 (m, 2H), 2.84-2.75 (m, 1H), 2.61 (t, 2H), 2.10 (s, 3H),1.66-1.32 (m, 3H), 1.31-1.05 (m, 5H), 0.86 (t, 4H), 0.78- 0.71 (m, 2H),0.60-0.54 (m, 2H).

Example 299

N-Cyclopropyl-3-[3-({1-[2-({(2R)-2-hydroxy-3-[(2-hydroxyethyl)amino]propyl}oxy)phenyl]cyclopropyl}amino)-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide

a)N-Cyclopropyl-4-methyl-3-{3-[(1-{2-[(2R)-oxiran-2-ylmethoxy]phenyl}cyclopropyl)amino]-2-oxopyrazin-1(2H)-yl}benzamide

Potassium carbonate (216 mg) and cesium fluoride (36.5 mg) were added toN-cyclopropyl-3-(3-(1-(2-hydroxyphenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzamide(Example 167d, 500 mg) in DMF (9 mL) and stirred for 1 h.(R)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (311 mg) was added and thereaction stirred for 3 days. The reaction mixture was used withoutisolation/purification.

MS: APCI(+ve) 473 (M+H)⁺.

b)N-Cyclopropyl-3-[3-({1-[2-({(2R)-2-hydroxy-3-[(2-hydroxyethyl)amino]propyl}oxy)phenyl]cyclopropyl}amino)-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide

Ethanolamine (1 mL) was added toN-cyclopropyl-4-methyl-3-{3-[(1-{2-[(2R)-oxiran-2-ylmethoxy]phenyl}cyclopropyl)amino]-2-oxopyrazin-1(2H)-yl}benzamide(Example 299a, 7.81 g) in DMF (3 mL). The reaction was heated at 50° C.overnight. The reaction mixture was partitioned between water and DCM.The combined organics were dried (MgSO₄), filtered and evaporated.Purification by preparative HPLC (Xbridge column, eluting with agradient of acetonitrile in 0.2% (v/v) aqueous ammonia) gave the titleproduct (0.102 g) after solvent removal and trituration with diethylether.

¹H NMR δ (CD₃OD) 7.82-7.76 (m, 1H), 7.61-7.52 (m, 2H), 7.45-7.39 (m,1H), 7.21-7.14 (m, 1H), 6.93-6.81 (m, 3H), 6.57-6.53 (m, 1H), 4.20-4.11(m, 1H), 4.03-3.98 (m, 2H), 3.64-3.56 (m, 2H), 2.96-2.88 (m, 1H),2.85-2.68 (m, 4H), 2.11-2.07 (m, 3H), 1.28-1.07 (m, 4H), 0.79-0.71 (m,2H), 0.60-0.53 (m, 2H).

MS: APCI(+ve) 534 (M+H)±.

Example 300

N-Cyclopropyl-3-[3-{[1-(2-{[(2R)-3-(ethylamino)-2-hydroxypropyl]oxy}phenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide

The title compound was prepared using a similar method to that describedfor Example 299b from(R)—N-cyclopropyl-4-methyl-3-(3-(1-(2-(oxiran-2-ylmethoxy)phenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)benzamide(Example 299a) and ethylamine.

MS: APCI(+ve) 518 (M+H)⁺.

¹H NMR δ (CD₃OD) 7.80 (dd, 1H), 7.59 (s, 1H), 7.55 (dd, 1H), 7.42 (d,1H), 7.21-7.14 (m, 1H), 6.93-6.82 (m, 3H), 6.55 (d, 1H), 4.22-4.12 (m,1H), 4.00 (d, 2H), 2.94-2.87 (m, 1H), 2.84-2.72 (m, 2H), 2.70-2.60 (m,2H), 2.09 (s, 3H), 1.28-1.18 (m, 4H), 1.14-1.04 (m, 4H), 0.78-0.71 (m,2H), 0.60-0.53 (m, 2H).

Example 301

N-Cyclopropyl-3-[3-{[1-(2-{[(2R)-2-hydroxy-3-(methylamino)propyl]oxy}phenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide

The title compound was prepared using a similar method to that describedfor Example 299b from(R)—N-cyclopropyl-4-methyl-3-(3-(1-(2-(oxiran-2-ylmethoxy)phenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)benzamide(Example 299a) and methylamine.

MS: APCI(+ve) 504 (M+H)⁺.

¹H NMR δ (CD₃OD) 7.81-7.79 (m, 1H), 7.60 (d, 1H), 7.57-7.54 (m, 1H),7.43 (d, 1H), 7.21-7.16 (m, 1H), 6.93-6.83 (m, 3H), 6.57 (d, 1H),4.20-4.12 (m, 1H), 4.02-3.99 (m, 2H), 2.91-2.83 (m, 1H), 2.84-2.72 (m,2H), 2.40 (d, 3H), 2.10 (s, 3H), 1.28-1.13 (m, 4H), 1.14-1.09 (m, 1H),0.79-0.71 (m, 2H), 0.61-0.54 (m, 2H).

Example 302

N-Cyclopropyl-3-[3-({1-[2-({(2S)-2-hydroxy-3-[(2-hydroxyethyl)amino]propyl}oxy)phenyl]cyclopropyl}amino)-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide

a)N-Cyclopropyl-4-methyl-3-{3-[(1-{2-[(2S)-oxiran-2-ylmethoxy]phenyl}cyclopropyl)amino]-2-oxopyrazin-1(2H)-yl}benzamide

The subtitle compound was prepared using a similar method to thatdescribed for Example 299a fromN-cyclopropyl-3-(3-(1-(2-hydroxyphenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzamide(Example 167d) and (S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate.

MS: APCI(+ve) 473 (M+H)⁺.

b)N-Cyclopropyl-3-[3-({1-[2-({(2S)-2-hydroxy-3-[(2-hydroxyethyl)amino]propyl}oxy)phenyl]cyclopropyl}amino)-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide

The title compound was prepared using a similar method to that describedfor Example 299b fromN-cyclopropyl-4-methyl-3-{3-[(1-{2-[(2S)-oxiran-2-ylmethoxy]phenyl}cyclopropyl)amino]-2-oxopyrazin-1(2H)-yl}benzamide(Example 302a).

MS: APCI(+ve) 534 (M+H)⁺.

¹H NMR δ (CD₃OD) 7.80 (dd, 1H), 7.60 (d, 1H), 7.56 (dd, 1H), 7.43 (d,1H), 7.21-7.15 (m, 1H), 6.92 (d, 2H), 6.89-6.83 (m, 1H), 6.56 (d, 1H),4.23-4.12 (m, 1H), 4.01 (d, 2H), 3.63-3.58 (m, 2H), 2.97-2.90 (m, 1H),2.85-2.67 (m, 4H), 2.10 (s, 3H), 1.27-1.07 (m, 4H), 0.79-0.71 (m, 2H),0.60-0.54 (m, 2H).

Example 303

N-cyclopropyl-3-[3-{[1-(2-{[(2S)-3-(ethylamino)-2-hydroxypropyl]oxy}phenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide

The title compound was prepared using a similar method to that describedfor Example 299b fromN-cyclopropyl-3-[3-({1-[2-({(2S)-2-hydroxy-3-[(2-hydroxyethyl)amino]propyl}oxy)phenyl]cyclopropyl}amino)-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide(Example 302a).

MS: APCI(+ve) 518 (M+H)⁺.

¹H NMR δ (CD₃OD) 7.80 (dd, 1H), 7.59 (d, 1H), 7.55 (dd, 1H), 7.42 (d,1H), 7.20-7.15 (m, 1H), 6.91 (d, 1H), 6.88-6.82 (m, 2H), 6.55 (d, 1H),4.19-4.12 (m, 1H), 4.03-3.97 (m, 2H), 3.46 (q, 2H), 2.93-2.87 (m, 1H),2.82-2.71 (m, 2H), 2.70-2.59 (m, 2H), 2.09 (s, 3H), 1.28-1.19 (m, 3H),1.15 (t, 3H), 1.08 (td, 3H), 0.78-0.72 (m, 2H), 0.59-0.54 (m, 2H).

Example 304

N-Cyclopropyl-3-[3-{[1-(2-{[(2S)-2-hydroxy-3-(methylamino)propyl]oxy}phenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide

The title compound was prepared using a similar method to that describedfor Example 299b fromN-cyclopropyl-3-[3-({1-[2-({(2S)-2-hydroxy-3-[(2-hydroxyethyl)amino]propyl}oxy)phenyl]cyclopropyl}amino)-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide(Example 302a).

MS: APCI(+ve) 504 (M+H)⁺.

¹H NMR δ (CD₃OD) 7.80 (dd, 1H), 7.60 (d, 1H), 7.56 (dd, 1H), 7.42 (d,1H), 7.21-7.15 (m, 1H), 6.94-6.82 (m, 3H), 6.56 (d, 1H), 4.21-4.12 (m,1H), 4.04-3.96 (m, 2H), 2.92-2.83 (m, 1H), 2.83-2.71 (m, 2H), 2.40 (d,3H), 2.10 (s, 3H), 1.29-1.19 (m, 3H), 1.18-1.09 (m, 2H), 0.79-0.71 (m,2H), 0.60-0.54 (m, 2H).

Example 305

3-[3-{[1-(2-{[(2R)-2-Amino-3-hydroxypropyl]oxy}phenyl)-1-methylethyl]amino}-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-4-methylbenzamide

a)N-Cyclopropyl-4-methyl-3-[3-{[1-methyl-1-(2-{[(4S)-2-oxo-1,3-oxazolidin-4-yl]methoxy}phenyl)ethyl]amino}-2-oxopyrazin-1(2H)-yl]benzamide

A solution ofN-cyclopropyl-3-(3-(2-(2-hydroxyphenyl)propan-2-ylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzamide(Example 134, 0.5 g) in acetonitrile (10 mL) was treated with potassiumcarbonate (0.495 g) and (S)-(2-oxooxazolidin-4-yl)methyl4-methylbenzenesulfonate (0.324 g) under nitrogen. The resulting mixturewas stirred at 80° C. for 16 h. The reaction mixture was diluted withwater, and extracted with DCM. The organic layer was dried (MgSO₄),filtered and evaporated to afford the subtitle compound as a solid (0.6g).

MS: APCI(+ve) 518 (M+H)⁺.

b)3-[3-{[1-(2-{[(2R)-2-Amino-3-hydroxypropyl]oxy}phenyl)-1-methylethyl]amino}-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-4-methylbenzamide

A solution ofN-cyclopropyl-4-methyl-3-[3-{[1-methyl-1-(2-{[(4S)-2-oxo-1,3-oxazolidin-4-yl]methoxy}phenyl)ethyl]amino}-2-oxopyrazin-1(2H)-yl]benzamide(Example 305a) (0.6 g) in water (10 mL) and MeOH (10 mL) was treatedwith potassium hydroxide (0.130 g) under nitrogen. The resulting mixturewas stirred at 50° C. for 16 h. The reaction mixture was diluted withwater (200 mL), and extracted with ethyl acetate (250 mL). The organicphase was dried (MgSO₄), filtered and evaporated. Purification bypreparative HPLC (Phenomenex Gemini column, eluting with a gradient ofacetonitrile in 0.2% (v/v) aqueous ammonia) gave the title compound as asolid (0.105 g).

MS: APCI(+ve) 492 (M+H)⁺.

¹H NMR δ (DMSO-d₆) 8.49 (s, 1H), 7.93-7.82 (m, 1H), 7.79 (s, 1H),7.55-7.44 (m, 1H), 7.41-7.30 (m, 1H), 7.27-7.16 (m, 1H), 7.03-6.86 (m,3H), 6.73-6.59 (m, 2H), 4.74-4.53 (m, 1H), 4.00-3.85 (m, 1H), 3.86-3.72(m, 1H), 3.38-3.24 (m, 1H), 3.14-2.99 (m, 1H), 2.94-2.80 (m, 1H), 2.17(s, 3H), 1.94 (s, 6H), 1.74-1.52 (m, 2H), 0.76-0.64 (m, 2H), 0.63-0.51(m, 2H).

Example 306

N-Cyclopropyl-3-[3-{[1-(2-{[(2R)-2-(dimethylamino)-3-hydroxypropyl]oxy}phenyl)-1-methylethyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide

A solution of3-[3-{[1-(2-{[(2R)-2-amino-3-hydroxypropyl]oxy}phenyl)-1-methylethyl]amino}-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-4-methylbenzamide(Example 305, 0.25 g) in dichloroethane (10 mL) was treated with 37%aqueous formaldehyde (0.021 mL) under nitrogen. The resulting mixturewas stirred at 20° C. for 10 minutes before adding sodiumtriacetoxyborohydride (0.323 g). The resulting mixture was stirred at20° C. for 16 h. The reaction mixture was diluted with water (125 mL),and extracted with DCM (250 mL). The organic phase was dried (MgSO₄),filtered and evaporated. Purification by preparative HPLC (PhenomenexGemini column, eluting with a gradient of acetonitrile in 0.2% (v/v)aqueous ammonia) gave the title compound as a solid (0.069 g).

MS: APCI(+ve) 520 (M+H)⁺.

¹H NMR δ (DMSO-d₅) 8.45 (s, 1H), 7.86 (d, 1H), 7.75-7.67 (m, 1H), 7.49(d, 1H), 7.31 (d, 1H), 7.24-7.15 (m, 1H), 7.01 (d, 1H), 6.92-6.84 (m,2H), 6.68-6.60 (m, 2H), 4.00-3.92 (m, 2H), 3.64-3.48 (m, 2H), 2.90-2.74(m, 2H), 2.24 (s, 6H), 2.05 (s, 3H), 1.77 (s, 6H), 0.74-0.64 (m, 2H),0.60-0.50 (m, 2H).

Example 307

N-Cyclopropyl-3-fluoro-5-[3-{[1-(2-{[(2R)-2-hydroxy-3-(methylamino)propyl}oxy}phenyl)-1-methylethyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide

a)N-Cyclopropyl-3-fluoro-4-methyl-5-[3-({1-methyl-1-[2-(2R)-(oxiran-2-ylmethoxy)phenyl]ethyl}amino)-2-oxopyrazin-1(2H)-yl]benzamide

Prepared fromN-cyclopropyl-3-fluoro-5-[3-[[1-(2-hydroxyphenyl)-1-methylethyl]amino]-2-oxo-1(2H)pyrazinyl]-4-methyl-benzamide(Example 252j) and (R)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate, usinga similar method to that described in Example 299a.

MS: APCI(+ve) 493 (M+H)⁺.

b)N-Cyclopropyl-3-fluoro-5-[3-{[1-(2-{[(2R)-2-hydroxy-3-(methylamino)propyl]oxy}phenyl)-1-methylethyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide

The title compound was prepared using a similar method to that describedfor Example 299b fromN-cyclopropyl-3-fluoro-4-methyl-5-[3-({1-methyl-1-[2-(2R)-(oxiran-2-ylmethoxy)phenyl]ethyl]amino)-2-oxopyrazin-1(2H)yl}benzamide(Example 307a).

MS: APCI(+ve) 524 (M+H)⁺.

¹H NMR δ (DMSO-d₆) 8.53 (s, 1H), 7.71 (d, 2H), 7.26 (d, 2H), 6.98-6.89(m, 3H), 6.68 (s, 2H), 4.84 (s, 1H), 3.93-3.88 (m, 3H), 2.91-2.78 (m,1H), 2.59-2.57 (m, 2H), 2.23 (s, 3H), 2.00 (s, 3H), 1.85 (s, 6H), 0.64(m, 4H).

Example 308

N-Cyclopropyl-3-[3-{[1-(2-{[(2R)-3-(ethylamino)-2-hydroxypropyl}oxy}phenyl)-1-methylethyl]amino}-2-oxopyrazin-1(2H)-yl]-5-fluoro-4-methylbenzamide

The title compound was prepared using a similar method to that describedfor Example 300 fromN-cyclopropyl-3-fluoro-4-methyl-5-[3-({1-methyl-1-[2-(2R)-(oxiran-2-ylmethoxy)phenyl]ethyl]amino)-2-oxopyrazin-1(2H)-yl]benzamide(Example 307a).

MS: APCI(+ve) 538 (M+H)⁺. ¹H NMR δ (DMSO-d₆) 8.52 (s, 1H), 7.75 (d, 1H),7.66 (s, 1H), 7.25 (d, 2H), 6.97-6.89 (m, 3H), 6.68 (s, 2H), 4.83 (s,1H), 3.88 (s, 3H), 2.92-2.79 (m, 1H), 2.68-2.57 (m, 4H), 2.00 (s, 3H),1.85 (s, 6H), 0.95 (s, 3H), 0.63 (m, 4H)

Example 309

N-Cyclopropyl-3-[3-{[1-(2-{[(2S)-3-(ethylamino)-2-hydroxypropyl]oxy}phenyl)-1-methylethyl]amino}-2-oxopyrazin-1(2H)-yl]-5-fluoro-4-methylbenzamide

a)N-Cyclopropyl-3-fluoro-4-methyl-5-[3-({1-methyl-1-[2-(2S)-(oxiran-2-ylmethoxy)phenyl]ethyl}amino)-2-oxopyrazin-1(2H)-yl]benzamide

The subtitle compound was prepared using a similar method to Example299a fromN-cyclopropyl-3-fluoro-5-[3-[[1-(2-hydroxyphenyl)-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide(Example 252j) and (S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate.

MS: APCI(+ve) 493 (M+H)⁺.

b)N-Cyclopropyl-3-[3-{[1-(2-{[(2S)-3-(ethylamino)-2-hydroxypropyl]oxy}phenyl)-1-methylethyl]amino}-2-oxopyrazin-1(2H)-yl]-5-fluoro-4-methylbenzamide

The title compound was prepared using a similar method to that describedfor Example 300 fromN-cyclopropyl-3-fluoro-4-methyl-5-[3-({1-methyl-1-[2-(2S)-(oxiran-2-ylmethoxy)phenyl]ethyl]amino)-2-oxopyrazin-1(2H)-yl]benzamide(Example 309a).

MS: APCI(+ve) 538 (M+H)⁺

¹H NMR δ (DMSO-d₆) 8.52 (s, 1H), 7.75 (d, 1H), 7.66 (s, 1H), 7.32 (d,1H), 7.19 (t, 1H), 6.97-6.86 (m, 3H), 6.68 (q, 2H), 4.83 (s, 1H),3.93-3.81 (m, 3H), 2.88-2.82 (m, 1H), 2.68-2.55 (m, 4H), 1.99 (s, 3H),1.84 (s, 6H), 0.97-0.92 (m, 3H), 0.70 (m, 2H), 0.55 (m, 2H).

Example 310

N-Cyclopropyl-3-fluoro-5-[3-([1-(2-{[(2S)-2-hydroxy-3-(methylamino)propyl]oxy}phenyl)-1-methylethyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide

The title compound was prepared using a similar method to that describedfor Example 300 fromN-cyclopropyl-3-fluoro-4-methyl-5-[3-({1-methyl-1-[2-(2S)-(oxiran-2-ylmethoxy)phenyl]ethyl]amino)-2-oxopyrazin-1(2H)-yl]benzamide(Example 309a).

MS: APCI(+ve) 524 (M+H)⁺.

¹H NMR δ (DMSO-d₆) 8.52 (s, 1H), 7.75 (d, 1H), 7.65 (s, 1H), 7.32 (d,1H), 7.18 (t, 1H), 6.98-6.86 (m, 3H), 6.70-6.66 (m, 2H), 4.84 (s, 1H),3.93-3.88 (m, 3H), 2.88-2.82 (m, 1H), 2.61-2.54 (m, 2H), 2.23 (d, 3H),2.00 (s, 3H), 1.84 (s, 6H), 0.70 (m, 2H), 0.56 (m, 2H).

Example 311

3-[3-({1-[2-(2-Aminoethoxy)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide

The title compound was prepared using a similar method to that describedfor Example 259e from3-[3-[[1-[2-(2-chloroethoxy)phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-5-fluoro-4-methyl-benzamide(Example 252k).

MS: APCI(+ve) 480.2 (M+H)⁺.

¹H NMR δ (DMSO-d₆) 8.61-8.44 (m, 1H), 7.77 (d, 1H), 7.68 (s, 1H),7.40-7.30 (m, 1H), 7.24-7.15 (m, 1H), 6.99-6.87 (m, 3H), 6.73-6.61 (m,2H), 3.96-3.80 (m, 2H), 2.93-2.77 (m, 3H), 2.05 (s, 3H), 1.88 (s, 6H),0.76-0.64 (m, 2H), 0.62-0.50 (m, 2H).

Example 312

N-(2-{2-[1-({4-[5-(Cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-3-oxo-3,4-dihydropyrazin-2-yl}amino)-1-methylethyl]phenoxy}ethyl)glycine

A solution of3-(3-(2-(2-(2-aminoethoxy)phenyl)propan-2-ylamino)-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-5-fluoro-4-methylbenzamide(Example 311, 0.17g) dissolved in THF (10 mL) was treated withtriethylamine (0.049 mL) and methyl bromoacetate (0.034 mL) undernitrogen. The resulting mixture was stirred at 20° C. for 16 h. Thereaction mixture was diluted with 2M aqueous NaOH (2 mL) and methanol (2mL). The solution was stirred at room temperature for 1 h, acidifiedwith acetic acid and extracted with ethyl acetate (50 mL).

The organic layer was dried (MgSO₄) and evaporated. Purification bypreparative HPLC (Phenomenex Gemini column using a 95-5% gradient ofaqueous 0.2% ammonia in acetonitrile as eluent) gave the title compound(0.03 g).

MS: APCI(+ve) 538 (M+H)⁺.

¹H NMR (DMSO-d₆) 8.61-8.50 (m, 1H), 7.74-7.64 (m, 2H), 7.36 (d, 1H),7.24-7.14 (m, 1H), 7.01-6.85 (m, 3H), 6.69-6.62 (m, 1H), 6.58-6.52 (m,1H), 4.11-3.99 (m, 2H), 3.15 (s, 2H), 3.03 (t, 2H), 2.91-2.82 (m, 1H),1.94 (s, 3H), 1.81 (s, 6H), 0.71-0.57 (m, 4H)

Example 313

N-(2-{2-[1-({4-[5-(Cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-3-oxo-3,4-dihydropyrazin-2-yl}amino)-1-methylethyl]phenoxy}ethyl)-beta-alani ne

of the title compound was prepared from3-(3-(2-(2-(2-aminoethoxy)phenyl)propan-2-ylamino)-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-5-fluoro-4-methylbenzamide(Example 311) and methyl bromopropanoate using a similar method to thatdescribed for Example 312.

MS: APCI(+ve) 552.4 (M+H)⁺.

¹H NMR δ (DMSO-d₆) 8.73-8.59 (m, 1H), 7.78-7.65 (m, 2H), 7.35 (d, 1H),7.25-7.12 (m, 1H), 7.06-6.86 (m, 3H), 6.70-6.58 (m, 2H), 4.05-3.93 (m,2H), 3.03-2.90 (m, 2H), 2.86-2.73 (m, 3H), 2.18 (t, 2H), 2.05 (s, 3H),1.87 (s, 6H), 0.74-0.61 (m, 2H), 0.61-0.48 (m, 2H)

Example 314

3-[3-({1-[2-(2-Aminoethoxy)phenyl]cyclopropyl}amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide

The title compound was prepared from3-[3-[[1-[2-(2-chloroethoxy)phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-5-fluoro-4-methyl-benzamide(Example 259d) using a similar method to Example 259e.

MS: APCI(+ve) 478.2 (M+H)⁺.

¹H NMR δ (DMSO-d₆) 8.45 (1H, d), 7.73 (1H, d), 7.60 (1H, s), 7.53-7.45(2H, m), 7.19 (1H, t), 6.98-6.80 (4H, m), 6.76-6.72 (1H, m), 3.97 (2H,t), 2.94 (2H, t), 2.89-2.75 (1H, m), 1.96 (3H, s), 1.27-0.98 (4H, m),0.72-0.64 (2H, m), 0.57-0.51 (2H, m)

Example 315

N-Cyclopropyl-3-fluoro-5-[3-{[1-(2-{2-[(2-hydroxyethyl)(methyl)amino]ethoxy}phenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide

The title compound was prepared from3-[3-[[1-[2-(2-chloroethoxy)phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-5-fluoro-4-methyl-benzamide(Example 259d) using a similar method to Example 259e.

MS: APCI(+ve) 536.2 (M+H)⁺.

¹H NMR δ (DMSO-d₆) 8.45 (1H, d), 7.72 (1H, d), 7.60 (1H, s), 7.48 (1H,d), 7.28 (1H, s), 7.19 (1H, t), 6.96 (1H, d), 6.89-6.82 (2H, m), 6.74(1H, d), 4.35-4.26 (1H, m), 4.08 (2H, t), 3.55-3.45 (2H, m), 2.83 (2H,t), 2.54 (2H, t), 2.31 (3H, s), 1.96 (3H, s), 1.21-1.02 (4H, m),0.74-0.62 (2H, m), 0.57-0.48 (2H, m)

Example 316

3-Fluoro-N-methoxy-4-methyl-5-{3-[(1-methyl-1-{2-[2-(methylamino)ethoxy]phenyl}ethyl)amino]-2-oxopyrazin-1(2H)-yl}benzamide

a) Methyl3-fluoro-5-[3-{[1-(2-hydroxyphenyl)-1-methylethyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzoate

The subtitle compound was prepared from3-[5-Bromo-3-[[1-methyl-1-[2-(phenylmethoxy)phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-5-fluoro-4-methyl-benzoicacid, methyl ester (Example 252h) using the method of Example 252j.

¹H NMR δ (DMSO-d₆) 9.55 (s, 1H), 7.82 (d, 1H), 7.77 (s, 1H), 7.25 (d,1H), 7.09-6.94 (m, 2H), 6.80-6.66 (m, 4H), 3.94 (s, 3H), 2.10 (s, 3H),1.89 (s, 6H)

b) Methyl3-[3-({1-[2-(2-chloroethoxy)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1(2H)-yl]-5-fluoro-4-methylbenzoate

The subtitle compound was prepared from methyl3-fluoro-5-[3-{[1-(2-hydroxyphenyl)-1-methylethyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzoate(Example 316a) using the method of Example 252k.

MS: APCI(+ve) 474 (M+H)⁺.

c)3-[3-({1-[2-(2-Chloroethoxy)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1(2H)-yl]-5-fluoro-4-methylbenzoic acid

Lithium hydroxide monohydrate (0.177 g) in water (5.00 mL) was added tomethyl3-[3-({1-[2-(2-chloroethoxy)phenyl]-1-methylethyl]amino)-2-oxopyrazin-1(2H)-yl]-5-fluoro-4-methylbenzoate(Example 316b, 1.17 g) in THF (10 mL) and the reaction mixture wasstirred for 4 h at room temperature. Water was added and the solutionacidified with 2M HCl. This was extracted into ethyl acetate (2x). Thecombined organics were dried (MgSO₄), filtered and evaporated to affordthe subtitle compound as a solid (1 g).

MS: APCI(+ve) 460 (M+H)⁺.

d)3-[3-({1-[2-(2-Chloroethoxy)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1(2H)-yl]-5-fluoro-N-methoxy-4-methylbenzamide

To3-[3-({1-[2-(2-chloroethoxy)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1(2H)-yl]-5-fluoro-4-methylbenzoicacid (Example 316c, 0.13 g) in DMF (3 mL) was added0-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) (0.182 g) and N,N-diisopropylethylamine (0.148 mL). The reactionwas stirred for 15 min, then O-methylhydroxylamine hydrochloride (0.047g) was added. The reaction mixture was stirred at room temperatureovernight, then diluted with water and extracted with ethyl acetate. Theorganic layer was dried (MgSO₄), filtered and evaporated to afford thesubtitle compound (0.13 g).

MS: APCI(+ve) 489 (M+H)⁺.

e)3-Fluoro-N-methoxy-4-methyl-5-{3-[(1-methyl-1-{2-[2-(methylamino)ethoxy]phenyl}ethyl)amino]-2-oxopyrazin-1(2H)-yl}benzamide

The title compound was prepared from3-[3-({1-[2-(2-chloroethoxy)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1(2H)-yl]-5-fluoro-N-methoxy-4-methylbenzamide(Example 316d) using a similar method to that described for Example 167fbut using dioxane as solvent and a reaction time of 5 min.

MS: APCI(+ve) 484.2 (M+H)⁺.

¹H NMR δ (DMSO-d₆) 7.60 (d, 2H), 7.26 (d, 2H), 6.95-6.91 (m, 3H), 6.67(s, 2H), 3.96 (s, 2H), 3.70 (s, 3H), 2.84 (s, 2H), 2.27 (s, 3H), 2.00(s, 3H), 1.83 (s, 6H).

Example 317

N-Methoxy-4-methyl-3-{3-[(1-{2-[2-(methylamino)ethoxy]phenyl}cyclopropyl)amino]-2-oxopyrazin-1(2H)-yl}benzamide

a) Methyl3-[3-({1-[2-(2-chloroethoxy)phenyl]cyclopropyl}amino)-2-oxopyrazin-1(2H)-yl]-4-methylbenzoate

A solution of methyl3-(3-(1-(2-hydroxyphenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzoate(Example 167c) 0.45 g) dissolved in acetonitrile (8 mL) was treated withpotassium carbonate (1.589 g) and 1-bromo-2-chloroethane (0.953 mL)under nitrogen. The resulting suspension was stirred at 83° C. for 10 h.The reaction mixture was evaporated to dryness and diluted with water(300 mL), and extracted with DCM. The organic was dried (MgSO₄),filtered and evaporated to afford the subtitle compound as a foam (0.520g).

MS: APCI(+ve) 454 (M+H)⁺.

b)3-[3-({1-[2-(2-Chloroethoxy)phenyl]cyclopropyl}amino)-2-oxopyrazin-1(2H)-yl]-4-methylbenzoicacid

The subtitle compound was prepared from methyl3-[3-({1-[2-(2-chloroethoxy)phenyl]cyclopropyl}amino)-2-oxopyrazin-1(2H)-yl]-4-methylbenzoate (Example 317a) using a similar method to that described inExample 316c.

MS: APCI(+ve) 440 (M+H)⁺.

¹H NMR δ (DMSO-d₆) 7.95 (dd, 1H), 7.86 (s, 1H), 7.66 (d, 1H), 7.55 (d,1H), 7.29 (t, 1H), 7.05 (d, 1H), 6.99-6.94 (m, 2H), 6.86 (d, 1H), 4.35(t, 2H), 4.07-4.00 (m, 2H), 1.99 (s, 3H), 1.18 (t, 4H).

c)3-[3-({1-[2-(2-Chloroethoxy)phenyl]cyclopropyl}amino)-2-oxopyrazin-1(2H)-yl]-N-methoxy-4-methylbenzamide

The subtitle compound was prepared from3-[3-({1-[2-(2-chloroethoxy)phenyl]cyclopropyl}amino)-2-oxopyrazin-1(2H)-yl]-4-methylbenzoicacid (Example 317 b) using a similar method to that described forExample 316d.

MS: APCI(+ve) 469 (M+H)⁺.

d)N-Methoxy-4-methyl-3-{3-[(1-{2-[2-(methylamino)ethoxy]phenyl}cyclopropyl)amino]-2-oxopyrazin-1(2H)-yl}benzamide

The title compound was prepared from3-[3-({1-[2-(2-chloroethoxy)phenyl]cyclopropyl}amino)-2-oxopyrazin-1(2H)-yl]-4-methylbenzoicacid (Example 317c) using a similar method to that described for Example316e.

MS: APCI(+ve) 464 (M+H)⁺

¹H NMR δ (DMSO-d₆) 7.76 (d, 1H), 7.58 (s, 1H), 7.49 (d, 3H), 7.19 (t,1H), 6.96 (d, 1H), 6.85-6.85 (m, 2H), 6.69 (d, 1H), 4.06 (t, 2H), 3.67(s, 3H), 2.91 (t, 2H), 2.36 (s, 3H), 2.06 (s, 3H), 0.85 (d, 2H), 1.07(s, 2H).

Example 318

N-cyclopropyl-5-{3-[(1-{2-[2-(ethylamino)ethoxy]phenyl}cyclopropyl)amino]-2-oxopyrazin-1(2H)-yl}-2-fluoro-4-methylbenzamide

a) 5-Bromo-4-fluoro-2-methylaniline

A mixture of iron powder (4.30 g) and ammonium chloride (1.143 g) inwater (23 mL) was heated under reflux at 100° C. for 30 minutes. To thishot mixture was added 1-bromo-2-fluoro-4-methyl-5-nitrobenzene (5.00 g)slowly and then the reaction mixture was heated under reflux at 100° C.overnight. The mixture was cooled to room temperature, filtered througha pad of celite, and extracted with ethyl acetate (3×50 mL). The organicsolution was washed with water (3×100 mL) and brine (100 mL), dried(MgSO₄) and concentrated under reduced pressure to give the subtitlecompound (3.59 g) as a solid.

¹H NMR δ (CDCl₃) 6.86-6.79 (m, 2H), 3.49 (s, 2H), 2.11 (s, 3H)

b) 2-(5-Bromo-4-fluoro-2-methylphenylamino)acetonitrile

Hunig's Base (6.15 mL) was added to 5-bromo-4-fluoro-2-methylaniline(Example 318a, 3.59 g) in THF (50 mL) at room temperature followed bybromoacetonitrile (2.451 mL). The reaction was heated to refluxovernight. The reaction was cooled to room temperature and concentrated.2N HCl and DCM were added. The organic layer was separated and is dried(MgSO₄) and concentrated to give the subtitle compound as a solid (6.61g).

¹H NMR δ (CDCl₃) 6.92 (d, 1H), 6.80 (d, 1H), 4.13 (d, 2H), 3.78 (s, 1H),2.13 (s, 3H).

c) [(5-Bromo-4-fluoro-2-methylphenyl)amino]acetonitrile

To a solution of 2-(5-bromo-4-fluoro-2-methylphenylamino)acetonitrile(Example 318b, 4.00 g) dissolved in ethyl acetate (12 mL) was addedHunig's Base (14.37 mL), methanol (4 mL) and PdCl₂(dppf) (0.351 g). Theresulting mixture was stirred at 90° C. overnight under an atmosphere ofcarbon monoxide (5 bar). The cooled reaction mixture was evaporated todryness and the residue passed through a pad of silica, eluting with 1:1ethyl acetate:iso-hexane. The filtrate was evaporated in vacuo to givethe subtitle compound as a solid (4.71 g).

¹H NMR δ (CDCl₃) 7.19 (d, 1H), 6.95 (d, 1H), 4.19 (d, 2H), 3.93 (s, 3H),2.21 (s, 3H)

d) Methyl5-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-2-fluoro-4-methylbenzoate

To a stirred solution of oxalyl bromide (5.97 mL) in DCM (88 mL) at 0°C. under nitrogen was added dropwise a solution of[(5-bromo-4-fluoro-2-methylphenyl)amino]acetonitrile (Example 318c, 4.71g) in DCM (88 mL). The mixture was allowed to warm to room temperatureand stirred for 30 min before addition of DMF (0.328 mL). The reactionmixture was then heated under reflux overnight. The reaction mixture wascooled to 0° C., water (100 mL) was added over 15 min (caution), thenthe organic layer (+2 further DCM extracts) was separated, dried (MgSO₄)and then poured onto a silica pad and eluted with DCM. The solvents wereremoved in vacuo to give the subtitle compound (4.96 g).

¹H NMR δ (DMSO-d₆) 8.09 (s, 1H), 8.00 (d, 1H), 7.48 (d, 1H), 3.86 (s,3H), 2.18 (s, 3H)

e) Methyl5-[3-({1-[2-(benzyloxy)phenyl]cyclopropyl}amino)-5-bromo-2-oxopyrazin-1(2H)-yl]-2-fluoro-4-methylbenzoate

A solution of 1-(2-(benzyloxy)phenyl)cyclopropanamine (1.026 g) indioxane (10 mL) was treated with methyl5-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-2-fluoro-4-methylbenzoate (Example318d, 1.500 g) and Hunig's Base (0.936 mL) under nitrogen. The resultingsolution was stirred at 100° C. for 16 h. The cooled mixture was dilutedwith 2 M HCl and extracted with diethyl ether. The combined organicswere dried (MgSO₄) and evaporated to afford the subtitle compound (2.310g) as a foam.

MS: APCI(+ve) 580, 582 (M+H)⁺

¹H NMR δ (DMSO-d₆) 7.87-7.49 (m, 4H), 7.48-7.41 (m, 1H), 7.40-7.26 (m,3H), 7.25-7.16 (m, 1H), 7.06-7.00 (m, 2H), 6.93-6.85 (m, 1H), 5.22 (s,2H), 3.83 (s, 3H), 2.11 (s, 3H), 1.30-1.05 (m, 4H).

f) Methyl2-fluoro-5-[3-{[1-(2-hydroxyphenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzoate

To methyl5-[3-({1-[2-(benzyloxy)phenyl]cyclopropyl}amino)-5-bromo-2-oxopyrazin-1(2H)-yl]-2-fluoro-4-methylbenzoate(Example 318e, 2.310 g) in ethanol (30 mL) was added ammonium formate(3.53 g) and Pd/C (0.042 g). The reaction was heated at 75° C. for 3 h.Hunig's Base (3 mL) was added, and the reaction was heated at 90° C. for4 h. Additional catalyst, ammonium formate and hunigs base were added,and the reaction was heated at 90° C. for 4 h. The reaction mixture wasthen filtered warm, through a fibre glass filter, washing through with500 mL ethanol, followed by 500 mL DCM, followed by 500 mL 10%methanol/DCM. The DCM and MeOH/DCM filtrates were combined, evaporated,and the resulting residue partitioned between DCM and water. The organiclayer was separated, dried (MgSO₄), filtered, and evaporated to give thesubtitle compound as a solid (1.063 g).

MS: APCI(+ve) 410 (M+H)⁺.

¹H NMR δ (CDCl₃) 11.29 (s, 1H), 7.77 (d, 1H), 7.39 (dd, 1H), 7.23-7.18(m, 1H), 7.12 (d, 1H), 7.03 (s, 1H), 6.93-6.90 (m, 2H), 6.86 (td, 1H),6.42 (d, 1H), 3.90 (s, 3H), 2.17 (s, 3H), 1.37-1.23 (m, 4H)

g)N-Cyclopropyl-2-fluoro-5-[3-{[1-(2-hydroxyphenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide

Isopropylmagnesium chloride (5.19 mL of a 2.0 M solution in THF) wasadded over 20 min of a solution of cyclopropylamine (1.830 mL) andmethyl2-fluoro-5-[3-{[1-(2-hydroxyphenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzoate(Example 318f, 1.063 g) in THF (20 mL) stirring at room temperatureunder nitrogen. The reaction mixture was stirred for 1 h. Water and 2 MHCl were cautiously added and the volatiles removed in vacuo. Theresidue was basified with saturated aqueous sodium bicarbonate solutionand extracted into DCM. The organics were combined, dried (MgSO₄) andevaporated to give the subtitle compound (1.189 g).

MS: APCI(+ve) 435 (M+H)⁺.

¹H NMR δ (CDCl₃) 11.35 (s, 1H), 7.92 (d, 1H), 7.41-7.36 (m, 1H),7.24-7.17 (m, 1H), 7.08 (d, 1H), 7.03-7.01 (m, 1H), 6.94-6.92 (m, 1H),6.92-6.89 (m, 1H), 6.89-6.82 (m, 1H), 6.79-6.72 (m, 1H), 6.43-6.41 (m,1H), 2.97-2.86 (m, 1H), 2.18-2.14 (m, 3H), 1.41-1.23 (m, 4H), 0.92-0.83(m, 2H), 0.65-0.57 (m, 2H).

h)5-[3-({1-[2-(2-Chloroethoxy)phenyl]cyclopropyl}amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-2-fluoro-4-methylbenzamide

To a solution ofN-cyclopropyl-2-fluoro-5-[3-{[1-(2-hydroxyphenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide(Example 318g, 1.189 g) in acetonitrile (30 mL) was added potassiumcarbonate (3.78 g) followed by 1-bromo-2-chloroethane (4.54 mL). Thereaction was heated at 95° C. for 32 h under nitrogen. The reaction wascooled to room temperature, filtered through celite, and the cake washedwith further acetonitrile. The filtrate was collected and the solventsremoved in vacuo to give the subtitle compound (1.368 g).

MS: APCI(+ve) 497/498 (M+H)⁺.

¹H NMR δ (CDCl₃) 7.80 (d, 1H), 7.57 (dd, 1H), 6.98 (d, 1H), 6.87 (t,1H), 6.84-6.82 (m, 1H), 6.74 (d, 1H), 6.69-6.63 (m, 1H), 6.23 (d, 1H),4.25-4.20 (m, 2H), 3.84-3.80 (m, 2H), 2.86-2.80 (m, 1H), 2.08 (s, 3H),1.23-1.16 (m, 3H), 1.10-1.06 (m, 1H), 0.83-0.76 (m, 2H), 0.56-0.50 (m,2H).

i)N-Cyclopropyl-5-{3-[(1-{2-[2-(ethylamino)ethoxy]phenyl}cyclopropyl)amino]-2-oxopyrazin-1(2H)-yl}-2-fluoro-4-methylbenzamide

A solution of ethylamine (2.012 mL of 2M in THF) and5-[3-({1-[2-(2-chloroethoxy)phenyl]cyclopropyl}amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-2-fluoro-4-methylbenzamide(Example 318h, 100 mg) in dioxane (3 mL) was heated for 24 h at 100° C.in a sealed tube. Further ethylamine (2.012 mL of a 2M solution in THF)was added and the reaction was heated for a further 24 h. Purificationby preparative HPLC (Xbridge column eluting with a gradient ofacetonitrile in 0.2% (v/v) aqueous ammonia) gave the title compound as asolid (10 mg).

MS: APCI(+ve) 506.2 (M+H)⁺.

¹H NMR (DMSO-d₆) 8.33 (s, 1H), 7.52-7.28 (m, 4H), 7.23-7.14 (m, 1H),6.95 (d, 1H), 6.90-6.79 (m, 2H), 6.65 (s, 1H), 4.05 (s, 2H), 2.99-2.87(m, 2H), 2.79 (s, 1H), 2.67-2.58 (m, 2H), 2.08-1.98 (m, 2H), 1.30-1.12(m, 4H), 1.08-0.94 (m, 4H), 0.91-0.79 (m, 1H), 0.72-0.58 (m, 2H),0.56-0.45 (m, 2H).

Example 319

N-Cyclopropyl-2-fluoro-4-methyl-5-{3-[(1-{2-[2-(methylamino)ethoxy]phenyl}cyclopropyl)amino]-2-oxopyrazin-1(2H)-yl}benzamide

To a solution of5-[3-({1-[2-(2-chloroethoxy)phenyl]cyclopropyl}amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-2-fluoro-4-methylbenzamide(Example 318h, 100 mg) and methylamine, 40% by wt solution in water (0.1mL) in dioxane (1 mL) was added potassium iodide (33.4 mg). The reactionmixture was stirred at room temperature overnight, then heated at 40° C.overnight. The reaction was heated at 50° C. for 48 h. Purification bypreparative HPLC (Phenomenex Gemini, eluting with a gradient ofacetonitrile in 0.2% (v/v) aqueous ammonia, followed by Xbridge columneluting with a gradient of acetonitrile in 0.2% (v/v) aqueous ammonia)gave the title compound as a solid (17 mg).

¹H NMR δ (DMSO-d₆) 8.34 (s, 1H), 7.51-7.41 (m, 3H), 7.33 (d, 1H), 7.19(t, 1H), 6.95 (d, 1H), 6.88-6.81 (m, 2H), 6.64 (d, 1H), 4.09-4.00 (m,2H), 2.94-2.85 (m, 2H), 2.83-2.75 (m, 1H), 2.35 (s, 3H), 2.03 (s, 3H),1.24-1.00 (m, 4H), 0.71-0.61 (m, 2H), 0.55-0.48 (m, 2H).

MS: APCI(+ve) 492.2 (M+H)+.

Example 320

N-Cyclopropyl-3-fluoro-4-methyl-5-[3-{[1-methyl-1-(2-{[2-(methylamino)ethyl]sulfanyl}phenyl)ethyl]amino}-2-oxopyrazin-1(2H)-yl]benzamide

a) 2-(Benzyloxy)ethanethiol

Potassium carbonate (11.20 g) was added to S-2-(benzyloxy)ethylethanethioate (8.52 g) in methanol (170 mL)/water (85 mL) and thereaction was stirred for 20 min. Water was added and the mixtureextracted with ethyl acetate. The organic layers were combined, washedwith aqueous ammonium chloride and dried (MgSO₄) and concentrated invacuo to give the subtitle compound (6.64g).

¹H NMR δ (CDCl₃) 7.33-7.24 (m, 5H), 4.54 (s, 2H), 3.61 (q, 2H), 2.72 (q,2H), 1.59 (t, 1H)

b) 2-([2-(Benzyloxy)ethyl]sulfanyl}benzonitrile

A solution of 2-nitrobenzonitrile (5.85 g) in DMF (20 mL) was treatedwith 2-(benzyloxy)ethanethiol (Example 320a, 6.64 g) and a solution ofpotassium hydroxide (3.76 g) in water (5 mL) was added dropwise undernitrogen. The resulting mixture was stirred at 0° C. for 2 h. Thereaction was quenched with water and extracted into ethyl acetate. Thecombined organics were washed with brine, dried (MgSO₄), andconcentrated in vacuo. The residue was purified (SiO₂ chromatographyeluting with 50% diethyl ether in iso-hexane) to afford the subtitlecompound as a solid (7.08 g).

¹H NMR δ (CDCl₃) 7.60 (d, 1H), 7.46 (d, 2H), 7.32-7.23 (m, 6H),4.54-4.53 (m, 2H), 3.72 (t, 2H), 3.24 (t, 2H)

c) 2-(2-{[2-(Benzyloxy)ethyl]sulfanyl}phenyl)propan-2-amine

A suspension of cerium (III) chloride (9.15 g) dissolved in THF (40 mL)was stirred at 50° C. for 3 h under nitrogen. The resulting suspensionwas cooled and 2-{[2-(benzyloxy)ethyl]sulfanyl}benzonitrile (Example320b, 5 g) was added. The mixture was cooled to −10° C. before addingmethyllithium (1.5M solution as complex with lithium bromide, 30.9 mL).The mixture was kept at −10° C. for 30 min before quenching with 880ammonia (10 mL). The mixture was stirred at room temperature for 1 hthen the solid was filtered off and discarded. The filtrate was dilutedwith water and extracted with ethyl acetate. The organic layer was dried(MgSO₄), filtered and evaporated to afford the crude product. The crudeproduct was diluted with 2M aqueous HCl, extracted with diethyl ether(discarded). The aqueous layer was basified with 880 ammonia, extractedwith ethyl actetate. The organic layer was dried (MgSO₄), filtered andevaporated to afford the subtitle compound as an oil (3.20 g).

¹H NMR δ (CDCl₃) 7.47-7.43 (m, 2H), 7.30-7.26 (m, 5H), 7.15 (t, 2H),4.52 (s, 2H), 3.69 (t, 2H), 3.22 (t, 2H), 2.17 (s, 2H), 1.63 (s, 6H)

d) Methyl 3-[3-{[1-(2-([2-(benzyloxy)ethyl]sulfanyl}phenyl)-1-methylethyl]amino}-5-bromo-2-oxopyrazin-1(2H)-yl]-5-fluoro-4-methylbenzoate

The subtitle compound was prepared using a similar method to Example252h from methyl3-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-5-fluoro-4-methylbenzoate (Example252g) and 2-(2-{[2-(benzyloxy)ethyl]sulfanyl}phenyl)propan-2-amine(Example 320c).

MS: APCI(−ve) 639 (M−H)⁻.

e) 3-[3-{[1-(2-{[2-(Benzyloxy)ethyl]sulfanyl}phenyl)-1-methylethyl]amino}-5-bromo-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide

The subtitle compound was prepared from methyl3-[3-{[1-(2-{[2-(benzyloxy)ethyl]sulfanyl}phenyl)-1-methylethyl]amino}-5-bromo-2-oxopyrazin-1(2H)-yl]-5-fluoro-4-methylbenzoate(Example 320d) using a similar method to that described for Example252i. The crude product was triturated in diethyl ether and the solidfiltered off to give the subtitle product (2.22g) The filtrate wasconcentrated in vacuo then purified (SiO₂ chromatography eluting with100% diethyl ether to 100% ethyl acetate). The product containingfractions were combined and concentrated in vacuo to yield furthersubtitle compound (1.7 g) as a solid.

MS: APCI(+ve) 665 (M+H)⁺.

f)3-[3-{[1-(2-{[2-(Benzyloxy)ethyl]sulfanyl}phenyl)-1-methylethyl]amino}-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide

To3-[3-{[1-(2-{[2-(Benzyloxy)ethyl]sulfanyl}phenyl)-1-methylethyl]amino}-5-bromo-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide(Example 320e, 1.7 g) in ethanol (35 mL) was added ammonium formate(2.255 g) and Pd/C (0.544 g) and the resulting solution heated at 75° C.for 1 h. After cooling to room temperature, type 490 paste 10% Pd/C(0.272g) slurried in ethanol (5 mL) was added and the reaction heated to75° C. for 1 hr. The reaction was filtered through celite then thefiltrate concentrated in vacuo then extracted into DCM. The organicsolution was dried (MgSO₄) and concentrated in vacuo to give the subtitle compound (1.290 g).

MS: APCI(+ve) 587 (M+H)⁺.

g)N-Cyclopropyl-3-fluoro-5-{3-[(1-{2-[(2-hydroxyethyl)sulfanyl]phenyl}-1-methylethyl)amino]-2-oxopyrazin-1(2H)-yl}-4-methylbenzamide

3-[3-{[1-(2-{[2-(Benzyloxy)ethyl]sulfanyl}phenyl)-1-methylethyl]amino}-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide(Example 320f, 1.2 g) was stirred in DCM (120 mL) and cooled to 0° C.Boron tribromide (0.387 mL of a 1M solution in DCM) was added dropwiseat 0° C. and the reaction stirred for 30 min at 0° C. A further 4 eq ofboron tribromide solution was added after 1 h and the reaction warmed toroom temperature. The reaction mixture was diluted with ice water, andextracted with ethyl acetate. The organic layers were combined and dried(MgSO₄), filtered and evaporated in vacuo to afford the crude product.The crude product was purified (SiO2 chromatography eluting with 100%diethyl ether to 100% ethyl acetate) to afford the subtitle compound asa solid (0.6g).

MS: APCI(+ve) 497 (M+H)⁺.

h)N-Cyclopropyl-3-fluoro-4-methyl-5-[3-{[1-methyl-1-(2-{[2-(methylamino)ethyl]sulfanyl}phenyl)ethyl]amino}-2-oxopyrazin-1(2H)-yl]benzamide

N-Cyclopropyl-3-fluoro-5-{3-[(1-{2-[(2-hydroxyethyl)sulfanyl]phenyl}-1-methylethyl]amino]-2-oxopyrazin-1(2H)-yl}-4-methylbenzamide(Example 320g, 0.15 g) was stirred in DCM (20 mL) and cooled to −40° C.before triethylamine (0.046 mL) and methanesulfonyl chloride (0.024 mL)were added. The reaction was warmed to room temperature and methylamine(40% in water) and ethanol (5 mL) were added. The reaction was thenstirred for 18 h at 100° C. The reaction was concentrated in vacuo, thenpurified on SCX resin eluting with methanol (discarded) and flushingwith 20% ammonia in methanol. The crude product was purified bypreparative HPLC (Phenomenex Gemini column, eluent: 95-5% gradient ofaqueous 0.2% aqueous ammonia in acetonitrile). The fractions containingthe desired compound were evaporated to dryness to afford the titlecompound as a solid (3 mg).

¹H NMR δ (DMSO-d₆) 8.54 (s, 1H), 7.75 (d, 1H), 7.63 (s, 1H), 7.45 (d,1H), 7.31 (d, 1H), 7.17 (s, 2H), 6.86 (s, 1H), 6.59 (d, 2H), 2.97 (s,2H), 2.85 (s, 1H), 2.61 (s, 2H), 2.23 (s, 3H), 2.00 (s, 3H), 1.84 (d,6H), 0.63 (d, 4H) MS: APCI(+ve) 510 (M+H)⁺.

Example 321

3-{3-[(1-{2-[(2-Aminoethyl)sulfanyl]phenyl}-1-methylethyl)amino]-2-oxopyrazin-1(2H)-yl}-N-cyclopropyl-5-fluoro-4-methylbenzamide

a)3-{3-[(1-{2-[(2-chloroethyl)sulfanyl]phenyl}-1-methylethyl)amino]-2-oxopyrazin-1(2H)-yl}-N-cyclopropyl-5-fluoro-4-methylbenzamide

A solution ofN-cyclopropyl-3-fluoro-5-{3-[(1-{2-[(2-hydroxyethyl)sulfanyl]phenyl}-1-methylethyl)amino]-2-oxopyrazin-1(2H)-yl}-4-methylbenzamide(Example 320g, 0.15 g) dissolved in acetonitrile (2 mL) was treated withtriethylamine (0.048 mL) and triethylamine hydrochloride (4.16 mg) undernitrogen. The resulting solution was stirred at 0° C. before addingp-toluenesulfonyl chloride (0.055 g) over 5 min. Lithium chloride (0.064g) was then added and the mixture was stirred at room temperature for 16h. The reaction mixture was diluted with water (200 mL), and extractedwith DCM (200 mL). The organic layer was separated, dried (MgSO₄) andevaporated to afford the subtitle compound (0.14g).

MS: APCI(+ve) 516 (M+H)⁺.

b)3-{3-[(1-{2-[(2-Aminoethyl)sulfanyl]phenyl}-1-methylethyl)amino]-2-oxopyrazin-1(2H)-yl}-N-cyclopropyl-5-fluoro-4-methylbenzamide

The title compound was prepared from3-{3-[(1-{2-[(2-chloroethyl)sulfanyl]phenyl}-1-methylethyl]amino]-2-oxopyrazin-1(2H)-yl}-N-cyclopropyl-5-fluoro-4-methylbenzamide(Example 320a) using a similar method to that described for Example252l.

MS: APCI(+ve) 496 (M+H)⁺.

¹H NMR δ (DMSO-d₆) 8.54 (d, 1H), 7.75 (d, 1H), 7.62 (s, 1H), 7.45 (dd,1H), 7.32-7.29 (m, 1H), 7.19-7.14 (m, 2H), 6.86 (s, 1H), 6.59 (dd, 2H),2.91 (t, 2H), 2.87-2.84 (m, 1H), 2.63 (t, 2H), 2.00 (d, 3H), 1.84 (d,6H), 1.54 (s, 1H), 0.70 (q, 2H), 0.56 (q, 2H)

Example 322

N-Cyclopropyl-3-fluoro-5-[3-({1-[2-({2-[(2-hydroxyethyl)amino]ethyl}sulfanyl)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide

The title compound was prepared from ethanolamine and3-{3-[(1-{2-[(2-chloroethyl)sulfanyl]phenyl}-1-methylethyl]amino]-2-oxopyrazin-1(2H)-yl}-N-cyclopropyl-5-fluoro-4-methylbenzamide(Example 321a) using a similar method to that described for Example252l. The crude product was purified by preparative HPLC (X-Bridgecolumn eluting with 95-5% gradient of aqueous 0.2% ammonia inacetonitrile) to give the title compound as a solid.

MS: APCI(+ve) 540 (M+H)⁺.

¹H NMR δ (DMSO-d₆) 8.54 (d, 1H), 7.75 (d, 1H), 7.64 (s, 1H), 7.45 (d,1H), 7.32 (d, 1H), 7.21-7.13 (m, 2H), 6.84 (s, 1H), 6.59 (dd, 2H), 4.42(t, 1H), 3.39 (q, 2H), 2.98 (t, 2H), 2.85 (dq, 1H), 2.67 (t, 2H), 2.55(d, 2H), 2.00 (s, 3H), 1.84 (d, 6H), 0.70 (q, 2H), 0.56 (q, 2H)

Example 323

N-Cyclopropyl-3-fluoro-4-methyl-5-{3-[(1-methyl-1-{2-[3-(methylamino)propyl]phenyl}ethyl)amino]-2-oxopyrazin-1(2H)-yl}benzamide

a) (Z)-3-(2-Cyanophenyl)acrylic acid

A solution of 1-nitrosonaphthalen-2-ol (5 g) dissolved in THF (30 mL)was treated with p-toluenesulfonyl chloride (6.61 g) under nitrogen. Theresulting mixture was stirred at 20° C. for 1 h. The mixture was treatedwith a solution of sodium hydroxide (4.04 g) in water (30 mL) dropwiseover 30 min to keep temperature below 25° C. The reaction mixture wasdiluted with water (200 mL), and extracted with diethyl ether (200 mL)(discarded). The aqueous layer was acidified with 2M HCl, extracted withethyl acetate (200 mL), dried (MgSO₄), filtered and evaporated. Theresidue was triturated with 50% diethyl ether in isohexane to give thesubtitle compound as a solid (4.75 g).

¹H NMR δ (DMSO-d₆) 12.87 (s, 1H), 7.90-7.47 (m, 4H), 7.19 (d, J=79.0 Hz,1H), 6.24 (d, J=79.0 Hz, 1H).

b) 3-(2-Cyanophenyl)propanoic acid

A slurry of (Z)-3-(2-cyanophenyl)acrylic acid (Example 323a, 4.75 g) inethanol (50 mL) was added to 5% Palladium (0.292 g) in ethanol (50 mL)and hydrogenated under 2.0 bar hydrogen pressure for 2 h. The reactionmixture was filtered and the filtrate evaporated to dryness to affordthe sub title compound as a solid (4.36 g).

¹H NMR δ (DMSO-d₆) 7.78 (d, 1H), 7.68-7.62 (m, 1H), 7.50 (d, 1H),7.44-7.38 (m, 1H), 3.02 (t, 2H), 2.62 (t, 2H)

c) 2-(3-hydroxypropyl)benzonitrile

A solution of 3-(2-cyanophenyl)propanoic acid (Example 323b, 4.36 g) inDCM (40 mL) was treated with oxalyl chloride (3.26 mL) under nitrogen.The resulting solution was stirred at 20° C. for 1 h. The reactionmixture was evaporated to dryness, azeotroped with toluene. The solidwas dissolved in THF (30 mL) and sodium borohydride (1.883 g) was added.The mixture was stirred at 20° C. for 16 h. Further Sodium borohydride(1.883 g) added and stirred for 4 h. The reaction required a further 3days and a further sodium borohydride (18.83 g). The reaction mixturewas evaporated, diluted with water (200 mL), and extracted with ethylacetate (200 mL). The organic was dried (MgSO₄), filtered and evaporatedto give the subtitle compound as an oil (3.83 g).

¹H NMR δ (DMSO-d₆) 7.78 (d, 1H), 7.68-7.62 (m, 1H), 7.50 (d, 1H),7.44-7.38 (m, 1H), 3.02 (t, 2H), 2.62 (t, 2H)

d) 2-(3-(Benzyloxy)propyl)benzonitrile

A solution of 2-(3-hydroxypropyl)benzonitrile (Example 323c, 3.83g) inDMF (40 mL) under nitrogen was treated with 60% Sodium hydride (1.140 g)and stirred at room temperature for 1 h before adding benzyl bromide(2.83 mL). The resulting solution was stirred at 20° C. for 60 h. Thereaction mixture was diluted with water (200 mL), and is extracted withethyl acetate (200 mL). The organic was dried (MgSO₄), filtered andevaporated. The residue was purified (SiO₂ chromatography eluting with30% diethyl ether in isohexane). Pure fractions were evaporated todryness to afford the subtitle compound as an oil (2.3 g).

¹H NMR δ (CDCl₃) 7.60 (d, 1H), 7.51-7.45 (m, 1H), 7.39-7.33 (m, 3H),7.32-7.25 (m, 4H), 4.53 (s, 2H), 3.52 (t, 2H), 2.97 (t, 2H), 2.03-1.96(m, 2H)

e) 2-{2-[3-(Benzyloxy)propyl]phenyl}propan-2-amine

A suspension of Cerium(III) chloride (4.51 g) dissolved in THF (20 mL)was stirred at 50° C. for 3 h under nitrogen. The resulting suspensionwas cooled and 2-(3-(benzyloxy)propyl)benzonitrile (Example 323d, 2.3 g)added. The mixture was cooled to −10° C. before adding a 1.5 MMethyllithium as complex with lithium bromide (15.25 mL). The mixturewas kept at −10° C. for 30 min before quenching with 880 ammonia (10mL). The mixture was stirred at room temperature for 1 h beforefiltering off the solids (discarded). The filtrate was diluted withwater (100 mL), and extracted with ethyl acetate (200 mL). The organicwas dried (MgSO₄), filtered and evaporated to afford the subtitlecompound as an oil (2.05 g).

¹H NMR δ (CDCl₃) 7.48 (d, 1H), 7.40-7.07 (m, 8H), 4.57 (s, 2H), 3.59 (t,2H), 3.16-3.04 (m, 2H), 2.04-1.92 (m, 2H), 1.83-1.63 (m, 2H), 1.62 (s,6H).

f) Methyl3-{3-[(1-{2-[3-(benzyloxy)propyl]phenyl}-1-methylethyl)amino]-5-bromo-2-oxopyrazin-1(2H)-yl}-5-fluoro-4-methylbenzoate

The subtitle compound was prepared using a similar method to Example252h from methyl3-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-5-fluoro-4-methylbenzoate (Example252g) and 2-(2-(3-(benzyloxy)propyl)phenyl)propan-2-amine (Example323e). MS: APCI(+ve) 622 (M+H)±.

g)3-{3-[(1-{2-[3-(Benzyloxy)propyl]phenyl}-1-methylethyl)amino]-5-bromo-2-oxopyrazin-1(2H)-yl}-N-cyclopropyl-5-fluoro-4-methylbenzamide

The subtitle compound was prepared using a similar method to Example252i from methyl3-{3-[(1-{2-[3-(benzyloxy)propyl]phenyl}-1-methylethyl)amino]-5-bromo-2-oxopyrazin-1(2H)-yl}-5-fluoro-4-methylbenzoate(Example 323f).

¹H NMR δ (CDCl₃) 7.59-7.44 (m, 2H), 7.39-7.15 (m, 10H), 6.80 (s, 1H),6.29 (s, 1H), 4.52 (s, 2H), 3.56-3.44 (m, 2H), 2.97-2.78 (m, 3H), 2.08(s, 3H), 1.98-1.81 (m, 8H), 0.90-0.78 (m, 2H), 0.64-0.51 (m, 2H)

h)N-Cyclopropyl-3-fluoro-5-[3-({1-[2-(3-hydroxypropyl)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide

The subtitle compound was prepared using a similar method to Example252j from3-{3-[(1-{2-[3-(benzyloxy)propyl]phenyl}-1-methylethyl]amino]-5-bromo-2-oxopyrazin-1(2H)-yl}-N-cyclopropyl-5-fluoro-4-methylbenzamide(Example 323g).

MS: APCI(+ve) 479 (M+H)⁺.

i)3-[3-({1-[2-(3-Bromopropyl)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide

A solution ofN-cyclopropyl-3-fluoro-5-[3-({1-[2-(3-hydroxypropyl)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide(Example 323h) (0.4 g) dissolved in THF (10 mL) was treated with carbontetrabromide (0.277 g) under nitrogen. The resulting mixture was cooledto 0° C. before adding triphenylphosphine (0.219 g). The reactionmixture was stirred at room temperature for 16 h. The reaction mixturewas evaporated and the residue purified (SiO₂ chromatography elutingwith 50% DCM in ethyl acetate) to give the subtitle compound as a solid(0.135 g).

¹H NMR δ (CDCl₃) 7.65-7.56 (m, 1H), 7.55-7.46 (m, 1H), 7.43-7.34 (m,1H), 7.26-7.17 (m, 4H), 6.80-6.71 (m, 1H), 6.64-6.55 (m, 1H), 3.38 (t,2H), 3.08-2.82 (m, 3H), 2.14 (s, 3H), 1.91 (d, 6H), 1.29-1.18 (m, 2H),0.91-0.81 (m, 2H), 0.66-0.55 (m, 2H)

j)N-Cyclopropyl-3-fluoro-4-methyl-5-{3-[(1-methyl-1-{2-[3-(methylamino)propyl]phenyl}ethyl)amino]-2-oxopyrazin-1(2H)-yl}benzamide

The title compound was prepared from3-[3-({1-[2-(3-bromopropyl)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide(Example 323g) using a similar method to that described for Example259e.

MS: APCI(+ve) 492.4 (M+H)⁺.

¹H NMR δ (DMSO-d₆) 8.65-8.55 (m, 1H), 7.82 (d, 1H), 7.74 (s, 1H),7.51-7.41 (m, 1H), 7.25-7.14 (m, 3H), 7.10-6.99 (m, 1H), 6.76-6.65 (m,2H), 2.98-2.79 (m, 3H), 2.51-2.39 (m, 2H), 2.31 (s, 3H), 2.10 (s, 3H),1.91-1.79 (m, 6H), 1.59-1.47 (m, 2H), 0.81-0.69 (m, 2H), 0.67-0.55 (m,2H).

Example 324

N-Cyclopropyl-4-methyl-3-[3-(2-{2-[3-(methylamino)propoxy]phenyl}pyrrolidin-1-yl)-2-oxopyrazin-1(2H)-yl]benzamide

a)N-Cyclopropyl-3-{3-[2-(2-hydroxyphenyl)pyrrolidin-1-yl]-2-oxo-3,4-dihydropyrazin-1(2H)-yl}-4-methylbenzamide

ToN-cyclopropyl-3-(3-(2-(2-methoxyphenyl)pyrrolidin-1-yl)-2-oxopyrazin-1(2H)-yl)-4-methylbenzamide(Example 97, 0.993 g) in DCM (10 mL) was added boron tribromide (4.47 mLof a 1M solution in DCM) at 0° C. and the reaction stirred for 3 h.Further Boron tribromide (4.47 mL of a 1M solution in DCM) was added andthe reaction stirred for 3 h. Ice was added followed by water and theaqueous layer extracted with DCM then EtOAc. The aqueous layer wasneutralised to pH 7 and extracted with DCM then EtOAc and all thecombined organics dried (Na₂SO₄) and the solvent removed to give thesubtitle compound as a solid (0.786 g).

MS: APCI(+ve) 432 (M+H)⁺.

b)3-[3-{2-[2-(3-Chloropropoxy)phenyl]pyrrolidin-1-yl}-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-4-methylbenzamide

A solution ofN-cyclopropyl-3-{3-[2-(2-hydroxyphenyl)pyrrolidin-1-yl]-2-oxo-3,4-dihydropyrazin-1(2H)-yl}-4-methylbenzamide(Example 324a, 0.2 g) in acetonitrile (5 mL) was treated with potassiumcarbonate (0.642 g) and 1-bromo-3-chloropropane (0.459 mL) undernitrogen. The resulting suspension was stirred at 83° C. for 10 h. Thereaction mixture was diluted with water and extracted with ethylacetate. The organic layer was dried (MgSO₄), filtered and evaporated togive the subtitle compound (0.23g).

MS: APCI(+ve) 507 (M+H)⁺.

c)N-Cyclopropyl-4-methyl-3-[3-(2-{2-[3-(methylamino)propoxy]phenyl}pyrrolidin-1-yl)-2-oxopyrazin-1(2H)-yl]benzamide

3-[3-{2-[2-(3-Chloropropoxy)phenyl]pyrrolidin-1-yl}-2-oxopyrazin-1(2H)-yl]-N-cyclopropyl-4-methylbenzamide(Example 324b, 0.23g) and methylamine (1 mL) were heated in a CEM ismicrowave in dioxane at 110° C. for 15 min. The resulting solution wasconcentrated in vacuo and purification by preparative HPLC (X-Bridgecolumn using a 95-5% gradient of aqueous 0.2% ammonia in acetonitrile)gave the title compound as a solid (0.028 g).

MS: APCI(+ve) 502 (M+H)⁺.

¹H NMR δ (DMSO-d₆) 8.14 (s, 1H), 7.77 (d, 1H), 7.65-7.56 (m, 1H),7.42-7.31 (m, 1H), 7.10 (t, 1H), 6.92-6.77 (m, 4H), 6.57-6.57 (m, 1H),5.97-5.94 (m, 1H), 4.13-4.03 (m, 3H), 3.93-3.77 (m, 1H), 3.01 (s, 4H),2.87-2.81 (m, 1H), 2.65 (t, 2H), 2.28 (s, 3H), 2.09 (s, 1H), 1.88-1.79(m, 5H), 0.70-0.64 (m, 2H), 0.58-0.53 (m, 2H)

Example 325 and Example 326

(R)—N-Cyclopropyl-4-methyl-3-(3-(2-(2-(3-(methylamino)propoxy)phenyl)pyrrolidin-1-yl)-2-oxopyrazin-1(2H)-yl)benzamideand(S)—N—Cyclopropyl-4-methyl-3-(3-(2-(2-(3-(methylamino)propoxy)phenyl)pyrrolidin-1-yl)-2-oxopyrazin-1(2H)-yl)benzamide

The racemic mixture from Example 324 was purified by chiral HPLC(Chirobiotic V column, eluting 80:20 0.1% triethylamine in MeOH: 0.1%acetic acid in methanol) to give the two unassigned single enantiomers.

Isomer 1:

MS: APCI(+ve) 502.2 (M+H)⁺.

Chiral Purity 95.5% @ 220 nM by HPLC

and

Isomer 2

MS: APCI(+ve) 502.2 (M+H)⁺.

Chiral Purity 97.1% @ 220 nM by HPLC

Example 327

N-Cyclopropyl-4-methyl-3-[3-(2-{2-[2-(methylamino)ethoxy]phenyl}pyrrolidin-1-yl)-2-oxopyrazin-1(2H)-yl]benzamideTrifluoroacetate salt

a) Benzyl2-(2-(1-(4-(5-(cyclopropylcarbamoyl)-2-methylphenyl)-3-oxo-3,4-dihydropyrazin-2-yl)pyrrolidin-2-yl)phenoxy)ethyl(methyl)carbamate

Cesium carbonate (0.274 g) was added to a solution ofN-cyclopropyl-3-{3-[2-(2-hydroxyphenyl)pyrrolidin-1-yl]-2-oxo-3,4-dihydropyrazin-1(2H)-yl]-4-methylbenzamide(Example 324a, 0.18 g) and benzyl 2-chloroethyl(methyl)carbamate (0.096g) in acetonitrile (4 mL), and the reaction was heated at 90° C. for 72h. DCM and water were added, and the organic layer was separated, dried(Na₂SO₄) and the solvent removed in is vacuo. Purification (SiO₂chromatography eluting with 30-50% EtOAc in DCM) gave the subtitlecompound as an oil (0.122 g).

MS: APCI(+ve) 622 (M+H)⁺.

b)N-Cyclopropyl-4-methyl-3-[3-(2-{2-[2-(methylamino)ethoxy]phenyl}pyrrolidin-1-yl)-2-oxopyrazin-1(2H)-yl]benzamideTrifluoroacetate salt

A solution of benzyl2-(2-(1-(4-(5-(cyclopropylcarbamoyl)-2-methylphenyl)-3-oxo-3,4-dihydropyrazin-2-yl)pyrrolidin-2-yl)phenoxy)ethyl(methyl)carbamate(Example 327a, 0.122 g) in ethanol (10 mL) was pumped through a Pd/Ccartridge at 2 ml/min under max Hydrogen at 40° C. on an H cubehydrogenator. The solvents were evaporated. Purification by preparativeHPLC (Xbridge column, eluting with a gradient of acetonitrile in 0.2%(v/v) aqueous TFA) gave the title product as a solid (45 mg).

MS: APCI(+ve) 488 (M+H)⁺.

1H NMR δ (CD₃OD) 7.78 (dt, 1H), 7.70-7.38 (m, 1H), 7.34 (d, 1H),7.28-7.18 (m, 1H), 7.03-6.90 (m, 4H), 6.67-6.63 (m, 1H), 6.36-6.28 (m,1H), 4.49-4.27 (m, 2H), 4.24-4.07 (m, 1H), 3.97-3.79 (m, 1H), 3.44-3.33(m, 2H), 2.90-2.79 (m, 1H), 2.55-2.37 (m, 4H), 2.22-1.54 (m, 6H),0.85-0.75 (m, 2H), 0.66-0.56 (m, 2H).

Example 328

N-Cyclopropyl-3-fluoro-4-methyl-5-[3-{[(1R,2S)-2-methyl-1-phenyl-3-pyrrolidin-1-ylpropyl]amino}-2-oxopyrazin-1(2H)-yl]benzamide

a) (2R,3R)-3-Amino-2-methyl-3-phenylpropan-1-ol

N-[(1R,2R)-3-{[tert-butyl(diphenyl)silyl]oxy}-2-methyl-1-phenylpropyl]-2-methylpropane-2-sulfinamide(Example 136b, 1.46 g) was stirred in methanol (10 mL) and then Hydrogenchloride (4M in dioxane) (10 mL) added. The reaction was stirred at 70°C. for 7 h and then concentrated in vacuo. The crude product wasazeotroped with toluene then triturated in ether for 2 days after whichthe solvent was concentrated in vacuo to give the subtitle compound(0.47g).

¹H NMR δ (DMSO-d₆) 8.51 (s, 2H), 7.71-7.67 (m, 1H), 7.49-7.35 (m, 4H),4.18-4.14 (m, 1H), 3.24-3.07 (m, 2H), 2.14-2.10 (m, 1H), 0.97 (s, 3H)

b) Methyl3-[5-bromo-3-{[(1R,2R)-3-hydroxy-2-methyl-1-phenylpropyl]amino}-2-oxopyrazin-1(2H)-yl]-5-fluoro-4-methylbenzoate

To methyl3-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-5-fluoro-4-methylbenzoate (Example252g, 0.9 g) in THF (3 mL) was added(2R,3R)-3-amino-2-methyl-3-phenylpropan-1-ol (Example 328a, 0.389 g) andHunig's Base (0.374 mL) and the reaction stirred at 50° C. for 8 h. Thereaction mixture was diluted with ethyl acetate and washed with aqueousNaHCO₃. The organics were dried (MgSO₄) and concentrated in vacuo toleave the crude product which was triturated overnight in 2:1isohexane/diethyl ether to give the subtitle compound. Purification ofthe filtrate (SiO₂ chromatography eluting with 50-100% diethyl ether inisohexane) to give further subtitle compound (total 0.820 g).

MS: APCI(+ve) 506 (M+H)⁺.

c) Methyl3-[5-bromo-3-{[(1R,2R)-3-hydroxy-2-methyl-1-phenylpropyl]amino}-2-oxopyrazin-1(2H)-yl]-5-fluoro-4-methylbenzoate

The subtitle compound was prepared from methyl3-(5-bromo-3-((1R,2R)-3-hydroxy-2-methyl-1-phenylpropylamino)-2-oxopyrazin-1(2H)-yl)-5-fluoro-4-methylbenzoate(Example 328b) using a similar method to that described in Example 259b.

MS: APCI(+ve) 426 (M+H)⁺.

d) N-Cyclopropyl-3-fluoro-5-[3-{[(1R,2R)-3-hydroxy-2-methyl-1-phenylpropyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide

The subtitle compound was prepared from methyl3-fluoro-5-[3-{[(1R,2R)-3-hydroxy-2-15methyl-1-phenylpropyl]amino]-2-oxopyrazin-1(2H)-yl]-4-methylbenzoate(Example 328c) using a similar method to that described for Example252i.

MS: APCI(+ve) 451 (M+H)⁺.

e)N-cyclopropyl-3-fluoro-4-methyl-5-[3-{[(1R,2R)-2-methyl-3-oxo-1-phenylpropyl]amino}-2-oxopyrazin-1(2H)-yl]benzamide

A solution of Dess-Martin Periodinane (0.911 g) in DCM (8 mL) was addeddropwise to a solution ofN-cyclopropyl-3-fluoro-5-[3-{[(1R,2R)-3-hydroxy-2-methyl-1-phenylpropyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzamide(Example 328d, 0.64 g) in DCM (8 mL) at 22° C. The resulting mixture wasstirred at 22° C. for 30 min. The reaction mixture was quenched withsat. aqueous Na₂S₂O₃ and sat. aqeuous NaHCO₃ and stirred for a further15 min and then extracted into DCM. The organic extracts were combined,dried (MgSO₄) and concentrated in vacuo to give the subtitle compound asa solid (0.6g).

MS: APCI(+ve) 449 (M+H)⁺.

f)N-Cyclopropyl-3-fluoro-4-methyl-5-[3-{[(1R,2S)-2-methyl-1-phenyl-3-pyrrolidin-1-ylpropyl]amino}-2-oxopyrazin-1(2H)-yl]benzamide

Sodium triacetoxyborohydride (0.284 g) was added toN-cyclopropyl-3-fluoro-4-methyl-5-[3-{[(1R,2R)-2-methyl-3-oxo-1-phenylpropyl]amino}-2-oxopyrazin-1(2H)-yl]benzamide(Example 328e, 0.3 g), pyrrolidine (0.221 mL) and Hunig's Base (0.467mL) in DCM (15 mL). The resulting suspension was stirred at 22° C. for 2h. The reaction mixture was basified with satd sodium bicarbonatesolution before extracting with DCM. The combined organic phases wereconcentrated in vacuo and the residue purified by preparative HPLC(Phenominex column using a 75-5% gradient of aqueous 0.2% ammonia inacetonitrile as eluent). The fractions containing the desired compoundwere evaporated to dryness to afford the title compound as a solid(0.046g).

MS: APCI(+ve) 504 (M+H)⁺.

¹H NMR δ (DMSO-d₆) 9.14 (dd, 1H), 8.52 (dd, 1H), 7.77-7.62 (m, 2H),7.36-7.24 (m, 5H), 6.75-6.65 (m, 2H), 5.07-5.05 (m, 1H), 2.85 (q, 1H),2.56-2.53 (m, 4H), 2.45-2.37 (m, 3H), 2.01 (s, 2H), 1.95 (s, 1H), 1.73(t, 3H), 0.79 (d, 3H), 0.69 (t, 2H), 0.58-0.54 (m, 2H).

Example 329

N-Cyclopropyl-3-fluoro-4-methyl-5-[3-{[(1R,2S)-2-methyl-1-phenyl-3-piperidin-1-ylpropyl]amino}-2-oxopyrazin-1(2H)-yl]benzamide

The title compound was prepared fromN-cyclopropyl-3-fluoro-4-methyl-5-[3-{[(1R,2R)-2-methyl-3-oxo-1-phenylpropyl]amino}-2-oxopyrazin-1(2H)-yl]benzamide(Example 328e) and piperidine using a similar method to that describedfor Example 328f.

MS: APCI(+ve) 518 (M+H)⁺.

¹H NMR δ (DMSO-d₆) 9.30 (dd, 1H), 8.52 (dd, 1H), 7.78-7.74 (m, 1H), 7.65(d, 1H), 7.36-7.22 (m, 5H), 6.69 (dd, 2H), 5.08-5.05 (m, 1H), 2.84 (s,1H), 2.54-2.45 (m, 2H), 2.23-1.88 (m, 7H), 1.74-1.64 (m, 2H), 1.62-1.53(m, 2H), 1.41-1.34 (m, 2H), 0.86-0.75 (m, 3H), 0.72-0.67 (m, 2H),0.58-0.54 (m, 2H).

Example 330

4-Chloro-N-cyclopropyl-3-[3-[(1-methyl-1-(2-[2-(methylamino)ethoxy]phenyl}ethyl)amino]-2-oxopyrazin-1(2H)-yl]benzamide

a) Methyl 3-amino-4-chlorobenzoate

A solution of methyl 4-chloro-3-nitrobenzoate (10 g) dissolved in aceticacid (100 mL) was treated with Iron powder (10.36 g) under nitrogen. Theresulting mixture was stirred vigorously at 20° C. for 2 h. The reactionmixture was filtered through celite and the filtrate evaporated todryness to afford crude product. The residue was diluted with aqueoussodium bicarbonate solution (200 mL), and extracted with dichloromethane(250 mL). The organic layer was separated, dried (MgSO₄), filtered andevaporated to afford the sub title compound (8.41 g).

¹H NMR δ (CDCl₃) 7.47 (s, 1H), 7.37-7.24 (m, 3H), 4.29-3.95 (m, 2H),3.90 (s, 3H)

b) Methyl 4-chloro-3-{[ethoxy(oxo)acetyl]amino}benzoate

A suspension of methyl 3-amino-4-chlorobenzoate (Example 330a, 8.41 g)dissolved in ethyl acetate (80 mL) was treated with triethylamine (9.47mL) under nitrogen. The resulting mixture was stirred at 0° C. beforeadding ethyl oxalyl chloride (5.57 mL) dropwise over 5 min. Theresulting mixture was stirred for 1 h. The reaction mixture was dilutedwith water (100 mL), and extracted with ethyl acetate. The organic layerwas washed with 2M hydrochloric acid followed by saturated sodiumbicarbonate solution. The organic layer was dried (MgSO₄), filtered andevaporated to afford the crude product. The solid was triturated withdiethyl ether to give the subtitle compound (11.20 g).

¹H NMR δ (CDCl₃) 9.53-9.42 (m, 1H), 9.12 (s, 1H), 7.82 (d, 1H), 7.50 (d,1H), 4.45 (q, 2H), 3.96 (s, 3H), 1.45 (t, 3H)

c) Methyl4-chloro-3-{[[(2,2-dimethoxyethyl)amino](oxo)acetyl]amino}benzoate

A solution of methyl 4-chloro-3-{[ethoxy(oxo)acetyl]amino}benzoate(Example 330b, 11.2 g) dissolved in ethyl acetate (80 mL) was treatedwith aminoacetaldehyde dimethyl acetal (5.08 mL) under nitrogen. Theresulting mixture was stirred at 20° C. for 3 h. The reaction mixturewas diluted with diethyl ether (100 mL) and stirred at room temperatureovernight. The solid formed was filtered off and dried under vacuum toafford the subtitle compound (12.64 g).

¹H NMR δ (CDCl₃) 9.92 (s, 1H), 9.12 (s, 1H), 7.81 (d, 1H), 7.70-7.56 (m,1H), 7.50 (d, 1H), 4.44 (t, 1H), 4.00 (s, 3H), 3.54 (t, 2H), 3.48 (s,6H)

d) methyl 4-chloro-3-(2,3-dioxo-3,4-dihydropyrazin-1(2H)-yl)benzoate

A suspension of methyl4-chloro-3-{[[(2,2-dimethoxyethyl)amino](oxo)acetyl]amino}benzoate(Example 330c, 8.5 g) in acetic acid (26 mL) was treated withtrifluoroacetic acid (8.5 mL) under nitrogen. The resulting mixture wasstirred at 120° C. for 3 h. The mixture was quenched with water (20 mL)and the resulting solid filtered off to give the subtitle compound (8.00g).

¹H NMR δ (DMSO-d₆) 8.13-8.01 (m, 2H), 7.84 (d, 1H), 6.52-6.40 (m, 2H),3.93 (s, 3H)

e) methyl 3-(3-bromo-2-oxopyrazin-1(2H)-yl)-4-chlorobenzoate

A suspension of methyl4-chloro-3-(2,3-dioxo-3,4-dihydropyrazin-1(2H)-yl)benzoate (Example330d, 8 g) in DCM (80 mL) was treated with N,N-dimethylformamide (0.220mL) and oxalyl bromide (2.94 mL) dropwise over 5 min at room temperatureunder nitrogen. The resulting mixture was stirred at 20° C. for 16 h.The reaction mixture turned black and was evaporated to afford crudeproduct. Purification (SiO₂ chromatography eluting with 30% diethylether in dichloromethane) gave the subtitle compound (6.33 g).

¹H NMR δ (DMSO-d₆) 8.28 (s, 1H), 8.10 (d, 1H), 7.90 (d, 1H), 7.77 (d,1H), 7.32 (d, 1H), 3.83 (s, 1H)

f)Methyl-3-[3-({1-[2-(benzyloxy)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1(2H)-yl]-4-chlorobenzoate

A solution of methyl 3-(3-bromo-2-oxopyrazin-1(2H)-yl)-4-chlorobenzoate(Example 330e, 3 g) dissolved in toluene (15 mL) was treated withN-ethyldiisopropylamine (2.99 mL) and2-(2-(benzyloxy)phenyl)propan-2-amine (Example 198d 2.107 g) undernitrogen. The resulting mixture was stirred at 125° C. for 8 h in asealed tube. The reaction mixture was diluted with water (150 mL), andextracted with ethyl acetate (250 mL). The organic was dried (MgSO₄),filtered and evaporated to afford crude product. Purification (SiO₂chromatography eluting with 50% diethyl ether in isohexane) gave thesubtitle compound (2.230 g).

¹H NMR δ (DMSO-d₆) 8.10-7.99 (m, 2H), 7.85 (d, 1H), 7.43-7.27 (m, 5H),7.23-7.15 (m, 1H), 7.03 (d, 1H), 6.95-6.82 (m, 2H), 6.73-6.64 (m, 2H),5.16 (s, 2H), 3.92 (s, 3H), 1.81 (d, 6H)

g) 3-[3-({1-[2-(Benzyloxy)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1(2H)-yl]-4-chloro-N-cyclopropylbenzamide

A solution ofmethyl-3-[3-({1-[2-(benzyloxy)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1(2H)-yl]-4-chlorobenzoate(Example 330f, 2.23 g) dissolved in THF (30 mL) was treated withcyclopropylamine (2.261 mL) and 2.0M Isopropylmagnesium chloride (11.06mL) under nitrogen. The resulting solution was stirred at 20° C. for 2h. The reaction mixture was diluted with aqueous ammonium chloride (150mL), and extracted with dichloromethane (250 mL). The organic was dried(MgSO₄), filtered and evaporated to afford the subtitle compound (2.40g).

¹H NMR δ (DMSO-d₆) 8.61-8.54 (m, 1H), 7.99-7.93 (m, 2H), 7.81-7.75 (m,1H), 7.38-7.28 (m, 5H), 7.25-7.16 (m, 1H), 7.09-7.02 (m, 1H), 6.94-6.84(m, 2H), 6.73-6.66 (m, 2H), 2.90-2.83 (m, 1H), 1.86 (s, 6H), 0.74-0.66(m, 2H), 0.60-0.53 (m, 2H)

h)N-(sec-butyl)-4-chloro-3-[3-{(1-(2-hydroxyphenyl)-1-methylethyl]amino}-2-oxopyrazin-1(2H)-yl]benzamide

A solution of3-[3-({1-[2-(benzyloxy)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1(2H)-yl]-4-chloro-N-cyclopropylbenzamide(Example 330g, 2.23 g) dissolved in DCM (30 mL) was treated with borontribromide (8.43 mL of a 1M solution in DCM) at 0° C. under nitrogen.The resulting mixture was stirred at 0° C. for 1 h. The reaction mixturewas diluted with water (200 mL), and extracted with dichloromethane (250mL). The organic was dried (MgSO₄), filtered and evaporated to affordcrude product. The crude product was triturated with diethyl ether (50mL) to afford the subtitle compound (1.760 g).

¹H NMR δ (DMSO-d₆) 9.59-9.50 (m, 1H), 8.62-8.53 (m, 1H), 8.03-7.94 (m,2H), 7.84-7.75 (m, 1H), 7.29-7.20 (m, 1H), 7.10-7.01 (m, 2H), 6.83-6.69(m, 4H), 2.96-2.82 (m, 1H), 1.93 (s, 6H), 0.77-0.67 (m, 2H), 0.64-0.54(m, 2H)

i)4-Chloro-3-[3-({1-[2-(2-chloroethoxy)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropylbenzamide

A solution ofN-(sec-butyl)-4-chloro-3-[3-{[1-(2-hydroxyphenyl)-1-methylethyl]amino}-2-oxopyrazin-1(2H)-yl]benzamide(Example 330h, 1 g) dissolved in acetonitrile (10 mL) was treated withpotassium carbonate (3.15 g) and 1-bromo-2-chloroethane (1.896 mL) undernitrogen. The resulting suspension was stirred at 75° C. for 10 h. Thereaction mixture was evaporated to dryness, diluted with water (300 mL),and extracted with DCM. The organic layer was separated, dried (MgSO₄),filtered and evaporated to afford the crude product. The crude productwas triturated with 50% ether in isohexane to afford the subtitlecompound (1.100 g).

¹H NMR δ (DMSO-d₆) 8.61-8.52 (m, 1H), 8.02-7.93 (m, 2H), 7.78 (d, 1H),7.39-7.30 (m, 2H), 6.97-6.88 (m, 3H), 6.65 (d, 2H), 4.24-4.15 (m, 2H),3.98-3.89 (m, 2H), 2.90-2.81 (m, 1H), 1.89-1.81 (m, 6H), 0.74-0.65 (m,2H), 0.62-0.53 (m, 2H)

j)4-Chloro-N-cyclopropyl-3-[3-[(1-methyl-1-{2-[2-(methylamino)ethoxy]phenyl}ethyl)amino]-2-oxopyrazin-1(2H)-yl]benzamide

A solution of4-chloro-3-[3-({1-[2-(2-chloroethoxy)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropylbenzamide(Example 330i, 0.22 g) dissolved in acetonitrile (3 mL) was treated with40% aqueous methylamine (0.380 mL). The resulting mixture was stirred at100° C. for 16 h in a sealed tube. The reaction mixture was filtered andpurified by preparative HPLC (Phenominex Gemini column using a 95-5%gradient of aqueous 0.2% ammonia in acetonitrile as eluent). Thefractions containing the desired compound were evaporated to afford thetitle compound (0.087 g).

MS: APCI(+ve) 496 (M+H)⁺.

¹H NMR 6 (DMSO-d₆) 8.62-8.52 (m, 1H), 8.02-7.92 (m, 2H), 7.78 (d, 1H),7.33 (d, 1H), 7.19 (t, 1H), 6.99-6.85 (m, 3H), 6.71 (s, 2H), 4.03-3.89(m, 2H), 2.91-2.76 (m, 3H), 2.31 (s, 3H), 1.87 (s, 6H), 0.74-0.65 (m,2H), 0.60-0.51 (m, 2H)

The following Examples 331 to 334 (Table 15) were prepared using asimilar method to that described for Example 330 using4-chloro-3-[3-({1-[2-(2-chloroethoxy)phenyl]-1-methylethyl]amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropylbenzamide(Example 330i) and a suitable amine.

Example 331

4-Chloro-N-cyclopropyl-3-[3-{[1-(2-{2-[(2-hydroxyethyl)amino]ethoxy}phenyl)-1-methylethyl]amino}-2-oxopyrazin-1(2H)-yl]benzamide

Example 332

4-Chloro-N-cyclopropyl-3-[3-({1-[2-(2-{[(2R)-2-hydroxypropyl]amino]ethoxy)phenyl]-1-methylethyl]amino)-2-oxopyrazin-1(2H)-yl]benzamide

Example 333

4-Chloro-N-cyclopropyl-3-[3-[(1-{2-[2-(ethylamino)ethoxy]phenyl}-1-methylethyl]amino]-2-oxopyrazin-1(2H)-yl]benzamide

Example 334

3-[3-({1-[2-(2-Aminoethoxy)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1(2H)-yl]-4-chlora-N-cyclopropylbenzamide

TABLE 15

MS [M + H]⁺ Example R m/z ¹H NMR δ (DMSO-d₆) 331

526 8.66-8.56 (m, 1H), 8.07-7.96 (m, 2H), 7.84 (d, 1H), 7.38 (d, 1H),7.24 (t, 1H), 7.06-6.89 (m, 3H), 6.76 (s, 2H), 4.43 (t, 1H), 4.08-3.95(m, 2H), 3.52- 3.38 (m, 2H), 3.01-2.88 (m, 3H), 2.73- 2.60 (m, 2H), 1.94(s, 6H), 0.82- 0.69 (m, 2H), 0.68-0.55 (m, 2H) 332

540 8.65-8.56 (m, 1H), 8.06-7.97 (m, 2H), 7.82 (d, 1H), 7.37 (d, 1H),7.23 (t, 1H), 7.05-6.88 (m, 3H), 6.67 (s, 2H), 4.45-4.36 (m, 1H),4.10-3.93 (m, 2H), 3.74-3.57 (m, 1H), 3.01-2.85 (m, 3H), 2.52-2.45 (m,2H), 1.85 (s, 6H), 1.04 (d, 3H), 0.78-0.71 (m, 2H), 0.65-0.59 (m, 2H)333

510 8.68-8.57 (m, 1H), 8.07-7.96 (m, 2H), 7.83 (d, 1H), 7.39 (d, 1H),7.24 (t, 1H), 7.07-6.91 (m, 3H), 6.76 (s, 2H), 4.10-3.93 (m, 2H),3.01-2.84 (m, 3H), 2.67-2.56 (m, 2H), 1.93 (s, 6H), 0.95 (t, 3H),0.81-0.70 (m, 2H), 0.66- 0.56 (m, 2H) 334

482 8.58 (d, 1H), 7.99-7.92 (m, 2H), 7.77 (d, 1H), 7.33 (d, 1H), 7.18(t, 1H), 6.99- 6.85 (m, 3H), 6.65 (s, 2H), 3.95- 3.79 (m, 2H), 2.95-2.79(m, 3H), 1.78 (s, 6H), 0.77-0.65 (m, 2H), 0.59- 0.50 (m, 2H)

Physical Form Data DESCRIPTION OF FIGURES

FIG. 1: X-ray powder diffraction pattern of Form A of Example 167 freebase

FIG. 2: X-ray powder diffraction pattern of Form B of Example 167 freebase

FIG. 3: X-ray powder diffraction pattern of Form A of Example 259 freebase

FIG. 4: X-ray powder diffraction pattern of Form A of Example 260 freebase

FIG. 5: X-ray powder diffraction pattern of Form A of Example 163 freebase

FIG. 6: X-ray powder diffraction pattern of Form B of Example 163 freebase

FIG. 7: X-ray powder diffraction pattern of Form C of Example 163 freebase

FIG. 8: X-ray powder diffraction pattern of Form D of Example 163 freebase

FIG. 9: X-ray powder diffraction pattern of Form A of Example 163Saccharide Salt

FIG. 10: X-ray powder diffraction pattern of Form A of Example 163Tosylate Salt

FIG. 11: X-ray powder diffraction pattern of Form B of Example 163Tosylate Salt

FIG. 12: X-ray powder diffraction pattern of Form A of Example 163Hydrochloride Salt

Instrument Details:

XRPD data were collected using a PANalytical CubiX PRO machine.

XRPD-PANalytical CubiX PRO

Data was collected with a PANalytical CubiX PRO machine in 0-20configuration over the scan range 2° to 40° 2θ with 100-second exposureper 0.02° increment. The X-rays were generated by a copper long-finefocus tube operated at 45kV and 40 mA. The wavelength of the copperX-rays was 1.5418 Å. The Data was collected on zero background holderson which ˜2 mg of the compound was placed. The holder was made from asingle crystal of silicon, which had been cut along a non-diffractingplane and then polished on an optically flat finish. The X-rays incidentupon this surface were negated by Bragg extinction.

DSC thermograms were measured using a TA Q1000 Differential Scanningcalorimeter, with aluminium pans and pierced lids. The sample weightsvaried between 0.5 to 5 mg. The procedure was carried out under a flowof nitrogen gas (50 ml/min) and the temperature studied from 25 to 300°C. at a constant rate of temperature increase of 10° C. per minute.

GVS profiles were measured using a Dynamic Vapour Sorption DVS-1instrument. The solid sample ca. 1-5 mg was placed into a glass vesseland the weight of the sample was recorded during a dual cycle stepmethod (40 to 90 to 0 to 90 to 0% relative humidity (RH), in steps of10% RH).

Preparation of Example 167 Free Base:N-Cyclopropyl-4-methyl-3-[3-[[1-[2-[2-(methylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamideCrystalline Form A

3-(3-(1-(2-(2-Chloroethoxy)phenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-4-methylbenzamide(Example 167e, 5.00 g) dissolved in dioxane (15 mL) was treated withmethylamine (15 mL of a 40 wt % solution in water). The resultingsuspension was stirred at 100° C. for 4 h in an autoclave. The solutionwas evaporated to dryness. The crude product was purified (SiO₂chromatography, eluting with a 5:1:94 (v/v) mixture of methanol:triethylamine: dichloromethane respectively). The product containingfractions were evaporated in vacuo and re-purified by RPHPLC (Xterracolumn, 95-5% gradient of aqueous 0.2% ammonia in acetonitrile as mobilephase). The product containing fractions were combined and freeze driedto leave a solid. Trituration with diethyl ether followed by drying invacuo overnight gave the title compound as a white powder (3.14 g).

¹H NMR consistent with that described above in example 167

MS: APCI(+ve) 474 (M+H)⁺.

Elemental Analysis—Found (calculated): % C: 68.0 (68.5); % H: 6.7 (6.6);% N: 14.2 (14.8).

Analysis of Example 167 Free Base:N-Cyclopropyl-4-methyl-3-[3-[[1-[2-[2-(methylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamideCrystalline Form A

A sample of example 167 crystalline form A obtained by the proceduredescribed above was analysed by XRPD, DSC and GVS.

The melting temperature of example 167 Crystalline Form A as determinedby DSC gave a single endothermic event, occurring at 166° C. (±2° C.),with a water uptake of 1% (±0.2%) between RH of 0%-80%, as measured byGVS. An XRPD diffraction pattern of example 167 Crystalline Form A ispresented in FIG. 1.

Preparation and Analysis of Example 167 Free Base:N-Cyclopropyl-4-methyl-3-[3-[[1-[2-[2-(methylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamideCrystalline Form B

A sample of example 167 crystalline form B was obtained by slurryingexample 167 crystalline Form A in dioxane at room temperature (˜25° C.)and was analysed by XRPD. An XRPD diffraction pattern of example 167crystalline form B is presented in FIG. 2.

Preparation of Example 259 Free Base:N-Cyclopropyl-3-fluoro-4-methyl-5-[3-[[1-[2-[2-(methylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamideCrystalline Form A

3-[3-[[1-[2-(2-chloroethoxy)phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-5-fluoro-4-methyl-benzamide(Example 259d, 10 g) in dioxane (25 mL) was treated with methylamine (15mL of a 40 wt % aqueous solution). The resulting mixture was stirred at100° C. for 16 h in a sealed tube. The reaction mixture was cooled,filtered so and the solvents removed in vacuo to give crude product (˜10g). The crude product (˜8.0g) was purified by RPHPLC (Waters X-Bridgecolumn, 95-5% gradient of aqueous 0.2% ammonia in acetonitrile as mobilephase). The product containing fractions were combined, evaporated andtriturated with diethyl ether overnight. The white solid was collectedby filtration and dried in vacuo to afford the title compound (4.14 g).

NMR consistent with that described above in example 259.

MS: APCI(+ve) 492 (M+H)⁺.

Elemental Analysis—Found (calculated): % C: 65.9 (66.0); % H: 6.1 (6.2);% N: 14.2 (14.3).

Analysis of Example 259 free base:N-Cyclopropyl-3-fluoro-4-methyl-5-[3-[[1-[2-[2-(methylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamideCrystalline Form A

A sample of example 259 crystalline form A obtained by the proceduredescribed above was analysed by XRPD, DSC and GVS.

The melting temperature of example 259 crystalline form A as determinedby DSC gave a single endothermic event, occurring at 163° C. (±2° C.),with a water uptake of 0.4% (±0.2%) between RH of 0%-80%, as measured byGVS. An XRPD diffraction pattern of example 259 crystalline form A ispresented in FIG. 3

Preparation of Example 260 Free Base:N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[(2-hydroxyethyl)amino]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamideCrystalline Form A

3-[3-[[1-[2-(2-chloroethoxy)phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-5-fluoro-4-methyl-benzamide(Example 259d, 5 g) and ethanolamine (6.1 mL) were heated at 100° C. indioxane (20 mL) in a sealed tube for 16 h. Purification of the cooledsolution by preparative HPLC (Xterra column, eluting with a gradient ofacetonitrile in 0.2% (v/v) aqueous ammonia) gave the title product (2.95g) after solvent removal in vacuo and trituration with isohexane/diethylether (1:1 80 mL).

MS: APCI(+ve) 522 (M+H)⁺.

¹H NMR (DMSO-d₅) 8.46 (1H, d), 7.73 (1H, d), 7.61 (1H, s), 7.51 (1H, d),7.43 (1H, s), 7.19 (1H, t), 6.95 (1H, d), 6.92-6.80 (2H, m), 6.74 (1H,d), 4.44 (1H, s), 4.06 (2H, t), 3.51-3.43 (2H, m), 3.42-3.30 (1H, m),2.97 (2H, t), 2.90-2.77 (1H, m), 2.69 (2H, t), 1.97 (3H, s), 1.27-1.01(4H, m), 0.75-0.63 (2H, m), 0.57-0.50 (2H, m).

Elemental Analysis—Found (calculated): % C: 63.8 (64.5); H: 6.3 (6.2);N: 13.0 (13.4).

Analysis of Example 260 Free Base:N-Cyclopropyl-3-fluoro-5-[3-[[1-[2-[2-[(2-hydroxyethyl)amino]ethoxy]phenyl]cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamideCrystalline Form A

A sample of example 260 crystalline Form A obtained by the proceduredescribed above was analysed by XRPD, DSC and GVS.

The melting temperature of example 260 crystalline form A as determinedby DSC gave a single endothermic event, occurring at 206° C. (±2° C.),with a water uptake of 1.2% (±0.2%) between RH of 0%-80%, as measured byGVS. An XRPD diffraction pattern of example 260 crystalline form A ispresented in FIG. 4.

Preparation of Example 163 Free Base Crystalline Form A:N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamideCrystalline Form A

ToN-cyclopropyl-3-(3-(2-(2-hydroxyphenyl)propan-2-ylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzamide(Example 134, 4.3 g) in acetonitrile (5 mL) was added potassiumcarbonate (2.84 g) followed by benzyl 2-chloroethyl(methyl)carbamate(2.69 g) and the reaction heated at 85° C. for 16 h under nitrogen.After cooling to room temperature, the mixture was evaporated to drynessand the residue partitioned between water (20 mL) and DCM (20 mL). Theaqueous layer was separated and further extracted into DCM (2×20 mL).The combined organics were evaporated to leave crude benzyl2-(2-(2-(4-(5-(cyclopropylcarbamoyl)-2-methylphenyl)-3-oxo-3,4-dihydropyrazin-2-ylamino)propan-2-yl)phenoxy)ethyl(methyl)carbamate(3.50 g) as a gum. Ethanol (150 mL) and P/C (0.611 g of 5%) were addedand the reaction stirred under H2 atmosphere (2 bar) for 4 h. Themixture was filtered through Celite (washing pad with aliquots ofethanol) and the combined filtrates evaporated to leave the crudeproduct (2.1g). Recrystallisation from ethyl acetate gave the titleproduct (1.15 g) as a white solid.

MS: APCI(+ve) 476 (M+H)⁺.

Analysis of Example 163 Free Base Crystalline Form A:N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamideCrystalline Form A

A sample of crystalline example 163 crystalline form A obtained by theprocedure described above was analysed by XRPD (measured using PhilipsX-Pert MPD), DSC and GVS. The crystalline form was slurried in npropylacetate, Toluene and Methyl tertiary-butyl ether, with no changein crystal form.

The melting temperature of example 163 crystalline form A as determinedby DSC gave a double endothermic event, occurring at 155° C. (1^(st)onset) and 236° C. (2^(nd) onset) (±2° C.). GVS determination gave 5%weight increase (% w/w) at 80% RH (±0.2%).

An XRPD diffraction pattern of example 163 crystalline form A ispresented in FIG. 5.

Preparation of Example 163 Free Base Crystalline Form B:N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamideCrystalline Form B

3-[3-[[1-[2-(2-Chloroethoxy)phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide(Example 198e, 17.5 g) in dioxane (50 mL) was treated with 40%Methylamine solution (50 mL) under nitrogen. The resulting suspensionwas heated in a sealed system at 100° C. for 4 h. After cooling to roomtemperature, the solution was evaporated to dryness. The crude productwas purified by flash chromatography (SiO₂, eluent 10% methanol indichloromethane and 1% triethylamine).

Evaporation of the relevant fractions to dryness and trituration of theresidue in diethyl ether gave a solid which was filtered off and driedto give the title compound (12.5g) as an off white solid.

MS: APCI(+ve) 476 (M+H)⁺.

Analysis of Example 163 Free Base Crystalline Form B:N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamideCrystalline Form B

A sample of crystalline example 163 crystalline form B obtained by theprocedure described above was analysed by XRPD (measured usingPANalytical CubiX PRO), DSC and GVS.

The melting temperature of example 163 crystalline form B as determinedby DSC gave a double endothermic event, occurring at 162° C. and 225° C.(±2° C.). GVS determination gave 4.3% weight increase (% w/w) at 80% RH(±0.2%).

An XRPD diffraction pattern of example 163 crystalline form B ispresented in FIG. 6.

Preparation of Example 163 Free Base Crystalline Form C:N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamideCrystalline Form C

3-[3-[[1-[2-(2-Chloroethoxy)phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide(Example 198e, 17.5 g) in dioxane (50 mL) was treated with 40%Methylamine solution (50 ml) under nitrogen. The resulting suspensionwas heated in a sealed system at 100° C. for 4 h. After cooling to roomtemperature, the solution was evaporated to dryness. The crude productwas purified by flash chromatography (SiO₂, eluent 10% methanol indichloromethane and 1% triethylamine). Evaporation of the relevantfractions to dryness and trituration of the residue in diethyl ethergave a solid which was filtered off. The filtrate was collected andevaporated. This residue was purified by preparative HPLC (WatersX-Terra column using a 95-5% gradient of aqueous 0.2% ammonia inacetonitrile as eluent). The fractions containing the desired compoundwere evaporated to dryness. Further purification by preparative HPLC(phenomenex column, aqueous 0.2% ammonia in acetonitrile as eluent) andfreeze-drying of the relevant fractions gave a solid. This freeze driedmaterial readily dissolved in ethyl acetate (30 mL) at room temperatureand after stirring for 1 h some solid precipitated. The mixture was thenheated to at 85° C. for 1 h to effect dissolution and then cooled andstirred at room temperature for 1 week. The solid was filtered off anddried in vacuo at 40° C. to afford the title compound (2.20 g).

Analysis of Example 163 Free Base Crystalline Form C:N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamideCrystalline Form C

A sample of crystalline example 163 crystalline form C obtained by theprocedure described above was analysed by XRPD (measured usingPANalytical CubiX PRO), DSC and GVS.

The melting temperature of example 163 crystalline form C as determinedby DSC gave a single endothermic event, occurring at 168° C. (±2° C.).GVS determination gave 0.3% weight increase (% w/w) at 80% RH (±0.2%).

An XRPD diffraction pattern of example 163 crystalline form C ispresented in FIG. 7.

Preparation and Analysis of Example 163 Free Base Crystalline Form D:N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamideCrystalline Form D

N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamideCrystalline Form B was slurried in ethyl acetate for 1 week. The solidwas filtered off and dried in vacuo at 40° C. to give the titlecompound.

A sample of this example 163 crystalline form D obtained by theprocedure described above was analysed by XRPD (measured usingPANalytical CubiX PRO).

An XRPD diffraction pattern of example 163 crystalline form D ispresented in FIG. 8.

Preparation and Analyze of Example 163 Saccharide Salt Crystalline FormA:N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamideSaccharide Salt Crystalline Form A

N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamidewas dissolved in methanol, treated with saccharin (1 equiv), evaporatedto dryness and slurried in acetonitrile (0.5 mL) for 1 week. The mixturewas centrifuged and the solid filtered off to give the title compound. Asample of crystalline example 163 saccharide salt crystalline form Aobtained by the procedure described above was analysed by XRPD (measuredusing Philips X-Pert MPD) and DSC.

The melting temperature of example 163 saccharide salt crystalline formA as determined by DSC gave three endothermic events, occurring at 148°C., 167° C. and 207° C. (±2° C.).

An XRPD diffraction pattern of example 163 saccharide salt crystallineform A is presented in FIG. 9.

Preparation and Analysis of Example 163 Tosylate Salt Crystalline FormA:N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamideTosylate Salt Crystalline Form A

N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamidewas dissolved in methanol, treated with p-toluenesulfonic acid (1equiv), evaporated to dryness and slurried in acetonitrile (0.5 mL) for1 week. The mixture was centrifuged and the solid filtered off to givethe title compound.

A sample of crystalline example 163 tosylate salt crystalline form Aobtained by the procedure described above was analysed by XRPD (measuredusing Philips X-Pert MPD), DSC and GVS.

The melting temperature of example example 163 tosylate salt crystallineform A as determined by DSC gave a single endothermic event, occurringat 206° C. (±2° C.). GVS determination gave 0.1% weight increase (% w/w)at 80% RH (±0.2%).

An XRPD diffraction pattern of example 163 tosylate salt crystallineform A is presented in FIG. 10.

Preparation and Analysis of Example 163 Tosylate salt Crystalline FormB:N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamideTosylate salt Crystalline Form B

N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamidewas dissolved in methanol, treated with p-toluenesulfonic acid (1equiv), evaporated to dryness and slurried in THF (0.5 mL) for 1 week.The mixture was centrifuged and the solid filtered off to give the titlecompound. A sample of crystalline example 163 tosylate salt crystallineform B obtained by the procedure described above was analysed by XRPD(measured using Philips X-Pert MPD) and DSC.

The melting temperature of example 163 tosylate salt crystalline form Bas determined by DSC gave three endothermic events, occurring at 88° C.,166° C. and 177° C. (±2° C.)

An XRPD diffraction pattern of example 163 tosylate salt crystallineform B is presented in FIG. 11.

Preparation and Analysis of Example 163 Hydrochloride salt CrystallineForm A:N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamideHydrochloride Salt Crystalline Form A

N-Cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(methylamino)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzamidewas dissolved in methanol, treated with 4N HCl in dioxane (excess),evaporated to dryness and slurried in THF (0.5 mL) for 1 week. Themixture was centrifuged and the solid filtered off to give the titlecompound. A sample of crystalline example 163 HCl salt polymorph Aobtained by the procedure described above was analysed by XRPD (measuredusing Philips X-Pert MPD) and DSC.

The melting temperature of example 163 HCl salt polymorph A asdetermined by DSC gave three endothermic events, occurring at 43° C.,90° C. and 177° C. (±2° C.)

An XRPD diffraction pattern of example 163 HCl salt polymorph A ispresented in FIG. 12.

Pharmacological Analysis

The ability of the compounds of formula (I) to inhibit p38 kinase may bedetermined using the following biological assay:

P38 Alpha Enzyme Assay

Enzyme assays were performed in polypropylene 96 well plates. Thefollowing solutions were added to each well; 10 μL of compound dilutionsin assay buffer (20 mM HEPES pH 7.4, containing 20 mM magnesium acetate,0.005% (w/v) Tween-20, 10 mM DTT) containing 1% (v/v) DMSO or assaybuffer containing 1% (v/v) DMSO alone, 70 μL of assay buffer containing36 nM substrate (biotinylated-ATF2) and 10 μL of an appropriate dilutionof human active recombinant p38α-6His tagged. Depending on batch of p38,an appropriate dilution was typically a 5 nM solution to give a finalenzyme concentration of 0.5 nM. At this stage, background control wellsalso received 50 μL of AlphaScreen quench buffer (10 mM HEPES pH 7.4containing 100 mM EDTA, 0.2% (w/v) bovine serum albumin). The plate wascovered, pre-incubated for 4 h at 37° C. and the enzyme reactioninitiated by addition of 10 μL 1 mM ATP. After incubation for a further45 minutes at 37° C., the reaction was stopped by addition of 50 μLquench reagent and 50 μL of the quenched reaction mixture transferred toan opaque, white 96-well plate. Detection reagent, 25 μL of 10 mM HEPESpH 7.4 containing 100 mM EDTA, 0.2% (w/v) bovine serum albumin, 0.3 nManti phosphoATF2 antibody and 25 μg/mL of AlphaScreen protein A acceptorand donor beads, was added to all wells in a darkened room, the platesealed and left in the dark for between 5 and 24 h before AlphaScreenreadings were taken using a Perkin Elmer EnVision reader. The compoundsof the examples show greater than or equal to 50% inhibition of p38αand/or p38β at concentrations less than 10 μM.

The following table shows pIC₅₀ figures for the compounds of the presentinvention.

Example Example Example Example number pIC₅₀ * number pIC₅₀ * numberpIC₅₀ * number pIC₅₀ * 1 7.4 83 7.7 165 9.3 247 9.8 2 6.4 84 8.6 166 7.6248 10 3 6.1 85 6.4 167 9.7 249 9.9 4 6.1 86 8.1 168 9.9 250 9.7 5 5.987 7.7 169 9.9 251 10.1 6 6.5 88 6.4 170 8.9 252 10.1 7 6.2 89 7.6 1718.8 253 10.2 8 6.4 90 6.4 172 9.6 254 10.2 9 6.3 91 7.9 173 9 255 10.210 7.3 92 7.6 174 8.9 256 10.5 11 7.6 93 6.9 175 9 257 10.3 12 7 94 7.5176 8.7 258 10.4 13 7.2 95 7.7 177 9 259 10 14 6 96 8.5 178 8.8 260 10.315 7.8 97 8.7 179 8.9 261 10.5 16 6.7 98 7.8 180 9.6 262 10.2 17 6.6 997.1 181 9.2 263 10.3 18 8.2 100 7.3 182 9 264 10.1 19 6.6 101 7.4 183 9265 9.7 20 6.1 102 6.3 184 8.7 266 9.4 21 6.7 103 6.1 185 9.1 267 9.5 227 104 7.2 186 9 268 10 23 6.9 105 6.2 187 9.8 269 9.9 24 6.3 106 6.2 1889.2 270 9.9 25 5.5 107 6.1 189 9.2 271 9.9 26 7.8 108 6.3 190 9 272 8.527 6.4 109 7.2 191 9.6 273 9 28 6.2 110 6.7 192 9.2 274 8.7 29 7 111 7.1193 9.3 275 8.6 30 6.9 112 9.4 194 9.1 276 8.8 31 7 113 9.8 195 8.8 2778.5 32 6.8 114 6.6 196 8.9 278 9.9 33 7.5 115 6.9 197 9 279 10.1 34 6.4116 6.4 198 9.6 280 10.1 35 6.6 117 6.8 199 9.1 281 10.4 36 6.8 118 7.3200 9.2 282 10.3 37 6.1 119 6.6 201 9.1 283 9.7 38 8.9 120 6.4 202 9.2284 9.5 39 7.5 121 6 203 8.9 285 9.6 40 6.7 122 5.6 204 9.8 286 9.3 41 7123 7 205 9 287 9.3 42 6.4 124 6.9 206 9.3 288 8.4 43 7.1 125 6.2 2078.9 289 8.9 44 7.6 126 8.1 208 9.1 290 8.5 45 6.5 127 7.3 209 8.9 2918.5 46 8 128 8.2 210 9.5 292 8.4 47 7.2 129 7.7 211 9.6 293 9.5 48 7.5130 8.2 212 9.6 294 10 49 6.9 131 7.6 213 9.9 295 9.5 50 7 132 7.5 2149.1 296 9.1 51 7.5 133 6.8 215 9.6 297 9.4 52 6.3 134 8.9 216 9.4 29810.2 53 7.4 135 9.5 217 9.6 299 10 54 6.5 136 8.6 218 9.1 300 10.3 556.5 137 8.1 219 9.3 301 10.1 56 6.4 138 8.9 220 8.3 302 10 57 7.1 1398.7 221 6.7 303 10.1 58 7 140 8.6 222 9 304 10.2 59 7.2 141 8.8 223 8.1305 9.9 60 7.3 142 8.8 224 8.4 306 10.1 61 6.3 143 8.8 225 8.2 307 10.362 7 144 7.9 226 6.6 308 10.4 63 6.3 145 8.2 227 8.5 309 10.2 64 6.8 1468.9 228 6.8 310 10 65 7 147 9 229 8.6 311 10.1 66 6.5 148 8.1 230 10 3129.8 67 6.6 149 8.9 231 9.9 313 9.9 68 7.6 150 7.9 232 9.1 314 10.4 696.2 151 9.1 233 9.9 315 10 70 6.8 152 8.9 234 10.3 316 10.4 71 6.8 1539.2 235 9.7 317 10.1 72 7.2 154 9 236 10 318 8.2 73 7.1 155 9.1 237 9.9319 8.1 74 6.7 156 8.9 238 9.7 320 9.5 75 7.1 157 9 239 9.6 321 9.7 766.8 158 9 240 8.8 322 9.8 77 7.5 159 9.6 241 9.5 323 9.5 78 7.8 160 9.8242 9.7 324 8.1 79 7.7 161 9.2 243 9.4 325 8.9 80 7.9 162 9.4 244 9.2326 7.6 81 6.3 163 9.6 245 9.5 327 8 82 7.5 164 9.6 246 9.8 328 9 3299.6 330 9.4 331 9.6 332 9.7 333 9.5 334 9.3 * The standard deviation ofthe p38 enzyme inhibition assay is between 0.2 and 0.3 log units. ThepIC50 values in the above table are means of replicate determinationswhich were within 2 x SD (95% confidence) of each other.

1. A compound of formula (I):

wherein: R¹ and R² are independently selected from H, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo, CF₃, and CN; R^(1a) is H; R³ is H; R⁴ is selectedfrom H, methyl, ethyl, methoxy, ethoxy, Cl, Br, CN, phenyl, and CONH₂,wherein said methyl is optionally substituted with NR¹²R¹³; R⁵ isselected from heterocycloalkyl and NR¹⁶R¹⁷; R⁶ is selected from H,alkyl, (C₁-C₄)alkoxy, and (C₃-C₆)cycloalkyl; R⁷ is selected from H,(C₁-C₄)alkyl, (C₁-C₄)alkoxy, and (C₃-C₆)cycloalkyl; R¹⁶ is selected fromH, aryl, (C₃-C₇)cycloalkyl and

wherein said (C₃-C₇)cycloalkyl may be optionally substituted with anaryl group; R¹⁷ is selected from H, (C₁-C₆)alkyl, aryl, heteroaryl,heterocycloalkyl and (C₃-C₇)cycloalkyl, wherein said (C₁-C₆)alkyl may beoptionally substituted with 1, 2 or 3 groups independently selected from(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl, heterocycloalkyl, heteroaryl andNR²⁰R²¹; as to R²² and R²³: R²² and R²³ are independent substituentssuch that: R²² is selected from H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, OH,NR²⁹R³⁰, heterocycloalkyl and aryl, wherein said (C₁-C₆)alkyl may beoptionally substituted with 1, 2 or 3 R²⁸ groups; and wherein said arylmay be optionally substituted with 1, 2 or 3 groups independentlyselected from (C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo, CF₃ and OH; and R²³ isselected from H and (C₁-C₆)alkyl; or R²² and R²³, together with thecarbon atom to which they are attached, form a (C₃-C₇)cycloalkyl orheterocycloalkyl ring; X is a bond or a (CR²⁴R²⁵)_(n) group; as to R²⁴and R²⁵: R²⁴ and R²⁵ are independently selected from H, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, OH, heterocycloalkyl and NR³⁹R⁴⁰; or R²⁴ and R²⁵,together with the carbon atom to which they are attached, form aheterocycloalkyl ring; Z is an aryl or heteroaryl ring, wherein saidaryl or heteroaryl ring is substituted with R²⁶ and R²⁷; as to R²⁶ andR²⁷: R²⁶ and R²⁷ are independent substituents such that: R²⁶ is selectedfrom H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, OH, aryl, O-aryl, halo,heterocycloalkyl, O-heterocycloalkyl, heteroaryl, O-heteroaryl,cycloalkyl, O-cycloalkyl, S(O)_(p)R³⁴, NR³⁴R³⁵ and CONR³⁴R³⁵, whereinsaid (C₁-C₆)alkyl or said (C₁-C₆)alkoxy may be optionally substitutedwith 1, 2 or 3 groups independently selected from halo, OH,heterocycloalkyl or NR³⁴R³⁵; and R²⁷ is selected from H, halo and(C₁-C₆)alkyl, wherein said (C₁-C₆)alkyl may be optionally substitutedwith 1, 2 or 3 halo groups; or R²⁶ and R²⁷, together, form amethylenedioxy group when attached to adjacent carbon atoms of the arylor heteroaryl ring; each occurrence of R²⁸ is independently selectedfrom NR²⁹R³⁰, halo, CH₂CF₃, CF₃, heterocycloalkyl, (C₁-C₆)alkoxy, OR³⁶,COOR⁴², CONR³¹R³² and SO₂NR³⁷R³⁸; R²⁹ and R³⁰ are independently selectedfrom H, (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, SO₂R⁴¹ and C(O)R⁴¹, whereinsaid (C₁-C₆)alkyl may be optionally substituted with, OH, NR⁵⁶R⁵⁷ orheterocycloalkyl; as to R³¹ and R³²: R³¹ and R³² are independentlyselected from H, (C₁-C₆)alkyl and (C₃-C₇)cycloalkyl; or R³¹ and R³²,together with the nitrogen atom to which they are attached, form a 4 to7 membered ring, optionally containing a further heteroatom selectedfrom NR³³, S and O; as to R³⁴ and R³⁵: R³⁴ and R³⁵ are independentlyselected from H, (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, C-linkedheterocycloalkyl and C(O)O(C₁-C₆)alkyl, wherein said (C₁-C₆)alkyl may beoptionally substituted by OH, halo, (C₁-C₆)alkoxy, NR⁵⁸R⁵⁹, C(O)OH andheterocycloalkyl; or R³⁴ and R³⁵, together with the nitrogen to whichthey are attached, form a 4 to 7 membered ring; R³⁶ is selected from H,(C₁-C₆)alkyl and heterocycloalkyl, wherein said (C₁-C₆)alkyl may beoptionally substituted with heterocycloalkyl; R¹², R¹³, R²⁰, R²¹, R³³,R³⁷, R³⁸, R³⁹, R⁴⁰, R⁴¹ and R⁴² are independently selected from H and(C₁-C₆)alkyl; n is 1 or 2; each occurrence of p is independentlyselected from 0, 1 or 2; cycloalkyl is a non-aromatic carbocyclic ring,optionally fused to an aryl group, wherein said cycloalkyl ringoptionally contains, where possible, up to 2 double bonds; and wherein,unless otherwise stated, said cycloalkyl may be optionally substitutedwith 1 or 2 substituents independently selected from (C₁-C₆)alkyl,(C₁-C₆)alkoxy, OH, CN, CF₃, halo and NR⁴³R⁴⁴; heterocycloalkyl is aC-linked or N-linked 3 to 9 membered non-aromatic, mono- or bi-cyclicring, optionally fused to an aryl or heteroaryl group, wherein saidheterocycloalkyl ring: contains: 1 or 2 NR⁴⁵ atoms, one N— atom, one N—atom and one NR⁴⁵, one N— atom, one NR⁴⁵ and an S(O)_(p) or an O atom,one N— atom and an S(O)_(p) or an O atom, one S atom, or one O atom;optionally contains, where possible, 1 or 2 double bonds; and isoptionally substituted on carbon with 1 or 2 substituents independentlyselected from (C₁-C₆)alkyl, (C₁-C₆)alkoxy, OH, CN, CF₃, halo, ═O,NR⁴⁶R⁴⁷, —C(O)NR⁴⁶R⁴⁷, bivalent substituent —OCH₂CH₂O— (wherein theterminal oxygen atoms are attached to the same ring carbon atom),bivalent substituent —CH₂NHCH₂— (wherein the terminal carbon atoms areattached to the same ring carbon atom), atetrahydro-1,1-dioxido-3-thienyl group, and aryl, wherein said(C₁-C₆)alkyl may be optionally substituted by aryl, (C₁-C₆)alkoxy or OH;and wherein each aryl group may be optionally substituted with(C₁-C₆)alkoxy (which in turn may be optionally substituted by NR³⁴R³⁵),(C₁-C₆)alkyl, OH, CF₃ and halo; aryl is an aromatic ring containing 6 or10 carbon atoms; wherein, unless otherwise stated, said aryl may beoptionally substituted with 1, 2 or 3 substituents independentlyselected from (C₁-C₆)alkyl, (C₁-C₆)alkoxy, OH, halo, CN, CF₃ andNR⁴⁸R⁴⁹; heteroaryl is a 5, 6, 9 or 10 membered aromatic ring,containing from 1 or 2 N atoms and, optionally, an NR⁵⁰ atom, or oneNR⁵⁰ atom and an S or an O atom, or one S atom, or one O atom; wherein,unless otherwise stated, said heteroaryl may be optionally substitutedwith 1, 2 or 3 substituents independently selected from (C₁-C₆)alkyl,(C₁-C₆)alkoxy, OH, halo, CN, CF₃ and NR⁵¹R⁵²; R⁴⁵ is selected from H,(C₁-C₆)alkyl, C(O)(C₁-C₆)alkyl, C(O)O(C₁-C₆)alkyl and aryl, wherein said(C₁-C₆)alkyl is optionally substituted with a group selected from(C₁-C₃)alkoxy, OH, halo, heterocycloalkyl and NR²⁹R³⁰; and wherein saidC(O)O(C₁-C₆)alkyl is optionally substituted with an aryl group; R⁵⁰ isselected from H, (C₁-C₆)alkyl and C(O)O(C₁-C₆)alkyl, wherein said(C₁-C₆)alkyl may be optionally substituted with a group selected from(C₁-C₃)alkoxy, OH, halo, (C₃-C₆)cycloalkyl and NR⁵³R⁵⁴; R⁴³, R⁴⁴, R⁴⁶,R⁴⁷, R⁴⁸, R⁴⁹, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁶, R⁵⁷ and R⁵⁹ are eachindependently selected from H and (C₁-C₆)alkyl; R⁵⁸ is selected from Hand (C₁-C₆)alkyl wherein said (C₁-C₆)alkyl may be optionally substitutedwith a group selected from (C₁-C₃)alkoxy and OH; or a pharmaceuticallyacceptable salt thereof.
 2. A compound according to claim 1, or apharmaceutically acceptable salt thereof, wherein: R¹ is selected from Hand F, and R² is selected from (C₁-C₄)alkyl and F.
 3. A compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof,wherein R⁴ is H.
 4. (canceled)
 5. A compound according to claim 1, or apharmaceutically acceptable salt thereof, wherein: R¹⁶ is

and Z is an aryl ring substituted with R²⁶ and R²⁷. 6-15. (canceled) 16.A compound according to claim 2, or a pharmaceutically acceptable saltthereof, wherein R⁴ is H.
 17. A compound according to claim 2, or apharmaceutically acceptable salt thereof, wherein: R¹⁶ is

and Z is an aryl ring substituted with R²⁶ and R²⁷.